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Endothelial and Smooth Muscle Cell Ion Channels in Pulmonary Vasoconstriction and Vascular Remodeling

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Abstract

The pulmonary circulation is a low resistance and low pressure system. Sustained pulmonary vasoconstriction and excessive vascular remodeling often occur under pathophysiological conditions such as in patients with pulmonary hypertension. Pulmonary vasoconstriction is a consequence of smooth muscle contraction. Many factors released from the endothelium contribute to regulating pulmonary vascular tone, while the extracellular matrix in the adventitia is the major determinant of vascular wall compliance. Pulmonary vascular remodeling is characterized by adventitial and medial hypertrophy due to fibroblast and smooth muscle cell proliferation, neointimal proliferation, intimal, and plexiform lesions that obliterate the lumen, muscularization of precapillary arterioles, and in situ thrombosis. A rise in cytosolic free Ca2+ concentration ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction, while increased release of mitogenic factors, upregulation (or downregulation) of ion channels and transporters, and abnormalities in intracellular signaling cascades are key to the remodeling of the pulmonary vasculature. Changes in the expression, function, and regulation of ion channels in PASMC and pulmonary arterial endothelial cells play an important role in the regulation of vascular tone and development of vascular remodeling. This article will focus on describing the ion channels and transporters that are involved in the regulation of pulmonary vascular function and structure and illustrating the potential pathogenic role of ion channels and transporters in the development of pulmonary vascular disease. © 2011 American Physiological Society. Compr Physiol 1:1555‐1602, 2011.

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Figure 1. Figure 1.

Pulmonary angiogram (left) and cast (right) of a segment of arterial tree in human lung (A), and the proposed three schemes describing this complex structure by the Weibel model (B), the Strahler model (C), and the diameter‐defined Strahler's system (D).

Figure 2. Figure 2.

Electric circuit of model cell membrane and intracellular ion homeostasis. Single‐section (A) and parallel‐conductance (B) model of cell membrane. For the parallel‐conductance model, one assumes independent conductance channels for K+, Na+, and Cl. (C) Schematic diagram showing major ion channels and transporters that determine membrane potential as well as electrical and chemical gradients for K+, Na+, Ca2+, and Cl in pulmonary artery smooth muscle cells (PASMC). Resting membrane potential (Em) for a PASMC is −40 to −60 mV. EK, ENa, ECa, and ECl represent the equilibrium potentials for K+, Na+, Ca2+, and Cl, respectively. The size of the arrows indicates the driving force for the given ions. Inset, a diagram showing the channel protein embedded in the lipid membrane.

Figure 3. Figure 3.

Regulation of intracellular [Ca2+] (A) and the major causes of membrane depolarization (B) in pulmonary artery smooth muscle cells. SERCA, Ca2+‐Mg2+ ATPase (Ca2+ pump) in the SR/ER membrane; PM, Ca2+‐Mg2+ ATPase (Ca2+ pump) in the plasma membrane; NCX, Na+‐Ca2+ exchanger; RyR, ryanodine receptor; IP3R, inositol 1,4,5‐trisphosphate (IP3) receptor; Em, membrane potential.

Figure 4. Figure 4.

Topological structure of the Kv channel α‐subunit (A) and voltage‐dependent Ca2+ channels (VDCC) (B). (A) A planar representation of a Kv channel α‐subunit (a) and its interaction with other α‐subunits (b) and the β‐subunits (c) via the N‐terminal T1 domain. The graphs in b and c show a 4α‐tetramer and an 4α/4β‐octamers, respectively. The pore of the 4α‐tetramer is shown in b. (B) A planar representation of a VDCC subunit. Inset: diagrammatical representation of a VDCC channel in the plasma membrane with associated subunits. The pore region (P) forming between the S5 and S6 subunits is indicated in red.

Figure 5. Figure 5.

A rise in [Ca2+]cyt is a major trigger for pulmonary vasoconstriction. When [Ca2+]cyt rises in pulmonary artery smooth muscle cells, Ca2+ binds to calmodulin (CaM), which causes contraction by activating (or phosphorylating) myosin light chain kinase (MLCK) and indirectly causes the inhibition of myosin light chain phosphatase (MLCP) via Rho kinase (ROK). Activation of G protein‐coupled receptors (GPCR) can also cause Ca2+‐independent contraction (or Ca2+ sensitization) through the RhoA/ROK pathway.

Figure 6. Figure 6.

A rise in [Ca2+]cyt is an important stimulus of pulmonary artery smooth muscle cells proliferation. In addition to activating MLCK and causing contraction, cytosolic Ca2+ also activates CaM kinase (CaMK) and mitogen‐activated protein kinase (MAPK), as well as various transcription factors (e.g., NFAT, CREB, AP‐1 family members, and NF‐κB), to facilitate cell passage through the cell cycle and cause cell proliferation. The arrows in the inset indicate the Ca/CaM‐sensitive steps in the cell cycle. MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; PVR, pulmonary vascular resistance; PAP, pulmonary arterial pressure; SR/ER, sarcoplasmic (or endoplasmic) reticulum.

Figure 7. Figure 7.

Structure of transient receptor potential channel (TRPC). (A) Planar views of the TRPC1, TRPV1, and TRPM1 channel subunits. (B) Representative traces reflecting changes in [Ca2+]cyt (left panel) recorded in pulmonary artery smooth muscle cells (PASMC) before and during application of 10 μM cyclopiazonic acid (CPA), a SERCA inhibitor that depletes intracellular Ca2+ stores. 0 Ca2+, Ca2+‐free solution. The rise in [Ca2+]cyt due to store‐operated Ca2+ entry (SOCE) or capacitative Ca2+ entry (CCE) is indicated in the shadow area. The right panel shows representative whole‐cell currents recorded in human PASMC cells before (−CPA) and after (+CPA) depletion of intracelluarly stored Ca2+ from the SR using 10 μM CPA.

Figure 8. Figure 8.

Oligomerization and translocation of STIM to SR/ER‐plasma membrane junctions are the major mechanism involved in SOCE through Orai tetramer‐formed SOC. (A) The Ca2+ sensor EF‐hand domain in the N terminus of STIM has bound Ca2+ (red circles) when the SR/ER Ca2+ store is filled with Ca2+ (up to 1 mM). Depletion of Ca2+ from the SR/ER causes Ca2+ to unbind from the low‐affinity EF‐hand of STIM, which subsequently leads to STIM oligomerization and translocation to the SR/ER‐plasma membrane junctions. (B) STIM accumulation in the vicinity of Orai channel dimmers induces Orai channels to cluster in the adjacent plasma membrane. The C‐terminal effector domain of STIM causes Orai channels to open by direct binding of the distal coiled‐coil domain, and triggers Ca2+ entry. Two STIMs can activate a single SOC formed by an Orai tetramer; channel activation of Orai may involve a preliminary step of assembling Orai dimmers into a functional tetramer.

Figure 9. Figure 9.

Functional coupling of receptors,  transient receptor potential channel (TRPC) and NCX in caveolae in pulmonary artery smooth muscle cells (PASMC). (A) Electron microscopy graphs showing the structure of plasma membrane in PASMC isolated from normal subjects and patients with idiopathic pulmonary arterial hypertension (IPAH). IPAH PASMC have increased flask‐like invaginations of the plasma membrane consistent with the morphology of caveolae (indicated by arrows) and as determined by the number of caveoli per membrane length. (B) and (C) Schematic diagram depicting the caveolin‐1 binding domains of TRPC1 (B) and the potential mechanisms (C) that are involved in ligand‐mediated regulation of intracellular [Ca2+]cyt through G protein‐coupled receptors (GPCR), TRPC, and Na+/Ca2+ exchangers (NCX) in caveolae. CBM, cav1‐binding motif; PBD, protein 4‐binding domain; CSD, caveolin‐scaffolding domain; PM, the plasma membrane; ER/SR, endoplasmic reticulum and sarcoplasmic reticulum; G, G protein; IP3, inositol 1,4,5‐trisphosphate; IP3R, IP3 receptor; SERCA, SR/ER Ca2+‐Mg2+ ATPase; Cav‐1, caveolin‐1.

Figure 10. Figure 10.

Structure of K+ channels. Planar membrane topologies of single K+ channel subunits for voltage‐gated K+ (Kv) channels (A), Ca2+‐activated (BKCa) K+ channels (B), inward rectifier K+ (KIR) channels (C), and two‐pore domain (K2P) K+ channels (D), respectively. The pore‐forming loop is indicated and the voltage sensor in the transmembrane (TM) domain 4 for Kv and BKCa channels. Membrane topology of a K2P channel subunit featuring two pore regions, P1 and P2 and four TM‐spanning domains, M1 to 4 and cytoplasmic N‐ and C‐ termini (D). The ATP‐sensitive K+ (KATP) channels are heterooctamers formed by the pore‐forming KIR subunits and the regulatory subunits, SUR (e.g., Kir6.1/SUR2B and Kir6.2/SUR2B) (as shown in C).

Figure 11. Figure 11.

Structure of voltage‐gated Na+ channels. (A) Planar schematic diagram showing structural arrangement of Na+ channel α and β12 subunits. (B) Representative currents showing inward Na+ currents (INa) in human pulmonary artery smooth muscle cells (PASMC), elicited by depolarizing the cell from a holding potential of −70 mV to a series of test potentials ranging from −80 and +80 mV in 20 mV increments. The inset indicates the summarized I‐V relationship curve for INa. (C) Representative INa at 0 mV from PASMC before, during and after extracellular application of 1 μM tetrodotoxin.

Figure 12. Figure 12.

Ca2+‐activated Cl currents (IClCa) in pulmonary artery smooth muscle cells (PASMC). (A) A representative family of whole‐cell IClCa in PASMC elicited by a series of test potentials from −60 to +60 mV in 20‐mV increments (from a holding potential of −70 mV). The cells are superfused with Modified Kreb's solution (MKS) including 1.8 mM Ca2+. (B) Representative traces of IClCa recorded in PASMC superfused with MKS (Control and Recovery) and Ca2+‐free MKS with 10 mM BaCl2 (0Ca‐10Ba). Replacement of extracellular Ca2+ with Ba2+ significantly enhanced inward cation current, but abolished the outward Cl currents and the inward tail currents, which were carried by Cl influx and efflux, respectively, through ClCa channels. (C) The superimposed record of whole‐cell IClCa in PASMC before (Control) and during extracellular application of niflumic acid.

Figure 13. Figure 13.

Gap junction (GJ) and GJ channels in vascular smooth muscle and endothelial cells. The changes in membrane potential (Em) and [Ca2+]cyt due to Ca2+ influx or release in one smooth muscle cell (SMC) can be communicated to an adjacent SMC through GJ channels and to an endothelial cell (EC) through GJ channels in the myoendothelial junction (MEJ). Ca2+ and electrical signals can also go through GJ channels between ECs. In addition to Ca2+ and other cations/anions, GJ channels also allow small molecules to go through, for example, IP3, DAG, and other second messengers in the cytosol. ER, endoplasmic reticulum; SR, sarcoplasmic reticulum; δEm, changes in Em (i.e., membrane depolarization, hyperpolarization, or repolarization); ROC, receptor‐operated Ca2+ channels.

Figure 14. Figure 14.

Formation of gap junction (GJ) channels and topology of the connexin (Cx). (A) A schematic diagram showing how the hemichannels in the membrane of one cell interact with the hemichannels in another cell to form GJ channels. Not all hemichannels form GJ channels; the hemichannels can also function as a non‐selective cation/anion channels. (B) The Cx is a membrane protein with four transmembrane domains and cytoplasmic N‐ and C‐termini. There are multiple cysteine residues in the extracellular E1 and E2 segments that make the channel sensitive to the regulation of oxidation and reduction.

Figure 15. Figure 15.

Inhibition of K+ channels causes membrane depolarization and causes pulmonary vasoconstriction. (A) Close of K+ channels in pulmonary artery smooth muscle cells (PASMC) causes membrane depolarization, which subsequently opens VDCC, enhances Ca2+ influx, increases [Ca2+]cyt, and induces pulmonary vasoconstriction. Opening of K+ channels, on the other hand, causes membrane hyperpolarization (close to the K+ equilibrium potential), decreases VDCC activity and causes pulmonary vasodilation. (B) Representative records of whole‐cell K+ currents (a), membrane potential (Em, b) and [Ca2+]cyt (c) in PASMC before (control), during (4‐AP) and after (wash) extracellular application of 5 mM 4‐amynopyridine (4‐AP). A representative record of tension measurement in an isolated pulmonary arterial ring before, during, and after 4‐AP treatment is shown in d.

Figure 16. Figure 16.

Activity of K+ channel is involved in apoptotic volume decrease (AVD) and apoptosis. (A) Diagram showing the chronological order of morphological and biochemical changes during apoptotic stimulation. Activation of K+ channels leads to a loss of intracellular K+, which relieves the inhibitory effect of K+ on cytoplasmic caspases and nucleases, increases caspase‐mediated cleavage, and ultimately induces nuclear breakage and apoptosis. Activation of K+ channels also accelerates AVD, which further facilitates the process leading to apoptosis. (B) Changes in cell morphology before (Control) and during treatment with apoptosis inducers. Exposure of cells to pro‐apoptotic triggers activates K+ (and Cl) channels, induces AVD, and ultimately causes DNA fragmentation and nuclear breakage. The image on the right showing DAPI‐stained nuclei in pulmonary artery smooth muscle cells treated with staurosporine; the cells undergoing apoptosis (showing significant nuclear breakage) are indicated by arrows. The AVD due to K+ (Cl and H2O) efflux occurs prior to nuclear condensation and DNA fragmentation.

Figure 17. Figure 17.

Two pathways of apoptosis. When death receptors (DR) are activated (e.g., by Fas ligand), cleavage of procaspase 8 (and/or 10) to active caspase 8 is an important initial step to induce apoptosis. Cytochrome c (Cyt c), which can be released from the mitochondria to the cytosol when cells are exposed to UV light or when mitochondrial membrane potential (δΨm) is depolarized, activates cytoplasmic caspase 9. Active caspases 8 and 9 then activate caspases 3/6/7 and cause DNA fragmentation and nuclear breakage, and eventually cell death. Cytosolic cytochrome c also activates Kv channels, induces K+ loss, decreases cytosolic [K+], which increases caspase activity and accelerates AVD, and ultimately promote apoptosis .

Figure 18. Figure 18.

Cellular mechanisms by which acute hypoxia causes pulmonary vasoconstriction. (A) Multiple pathways are involved in hypoxia‐induced increase in [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMC). Acute hypoxia can enhance Ca2+ influx through receptor‐operated Ca2+ channels (ROC) by activating phospholipase C (PLC) and diacylglycerol (DAG), through voltage‐dependent Ca2+ channels (VDCC) by membrane depolarization due to inhibition of K+ (Kv and K2P) channels and activation of Ca2+‐activated Cl (ClCa) channels, and through store‐operated Ca2+ channels (SOC) by active depletion of Ca2+ from the SR/ER. Acute hypoxia can also enhance Ca2+ release from the SR/ER, lysosome and mitochondrial by activating IP3 receptors (IP3R) and ryanodine (RyR) receptors, producing pyridine nucleotides (cyclic adenosine diphosphate‐ribose, cADPR and nicotinic acid adenine dinucleotide phosphate, NAADP), and inhibiting electron transportation chain (ETC), respectively. Store depletion may also increase Na+ influx through SOC and increases cytosolic [Na+], which would subsequently stimulate inward Ca2+ transportation via the reverse mode of Na+/Ca2+ exchange (NCX). (B) Representative records of whole‐cell Kv currents (IK(V)), membrane potential (Em), and [Ca2+]cyt in PASMC before (normoxia), during (hypoxia) and after (recovery) exposure to hypoxia. (C) Acute hypoxia decreases IK(V) only in KCNA5‐transfected PASMC, but not in mesenteric artery smooth muscle cells (MASMC) transfected with KCNA5 gene.

Figure 19. Figure 19.

Cellular mechanisms by which chronic hypoxia causes pulmonary vascular remodeling and vasoconstriction. Chronic exposure to hypoxia downregulates Kv and K2P channels and upregulates Ca2+‐activated Cl (ClCa) channels in pulmonary artery smooth muscle cells (PASMC). The resultant membrane depolarization opens voltage‐dependent Ca2+ channels (VDCC) and increases [Ca2+]cyt. Chronic hypoxia also upregulates VDCC (α1C), transient receptor potential channel (TRPC1/3/4/6), and Orai2/STIM2 proteins in PASMC. The resultant augmentation of Ca2+ influx through these upregulated Ca2+ channels further increase [Ca2+]cyt and ultimately causes pulmonary vasoconstriction and vascular remodeling. Downregulation of K+ channels also contributes to pulmonary vascular remodeling by inhibiting AVD and apoptosis in PASMC.

Figure 20. Figure 20.

Schematic diagram showing the causes of elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH, A) and the angiographic and histological features of the pulmonary vasculature in IPAH patients (B). The angiogram show significant “loss” of small vessels in the IPAH patient (B, upper panels), which is mainly due to sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling characterized by medial and intimal hypertrophy, neointimal proliferation, and obliteration of small pulmonary arteries and arterioles (B, lower panels). EVG, elastic Van Gieson staining.

The images shown in B are reproduced from Ref. 1957.
Figure 21. Figure 21.

Patterns of vascular remodeling (A) and common histological changes in the pulmonary vasculature in patients with pulmonary hypertension (B). (A) The remodeling of a vessel to a larger lumen with the same wall thickness is termed “outward hypertrophic” (or eccentric hypertrophy), since cross‐sectional area is increased. Conversely, vessel narrowing with increased wall thickness occurs in chronic hypertension and may be “inward eutrophic” (e.g., smaller lumen with a somewhat thicker wall, but the same cross‐sectional area) or “inward hypertrophic” or “concentric hypertrophy” (i.e., smaller lumen with sufficient wall thickening to increase cross‐sectional area). A common assumption is that changes in cross‐sectional area indicate changes in wall mass (as implied by the terms “hypotrophic” or hypertrophic”). This, of course, is only correct if vessel length is not altered . (B) In the lung, pulmonary vascular remodeling consists in concentric hypertrophy, eccentric hypertrophy (associated with adventitial lesion and hypertrophy and extracellular matrix lesions), and obliteration of small vessels due to intimal lesions, plexiform lesions and in situ thrombosis. Concentric hypertrophy, in situ thrombosis and obliteration increase pulmonary vascular resistance (PVR) by narrowing the affected arterial lumen, while eccentric hypertrophy contributes to increasing PVR by increasing the wall stiffness or decreasing the vascular wall compliance (which is one of the major causes for reduced distention and recruitment in pulmonary circulation).

Figure 22. Figure 22.

Schematic diagram showing the pathogenic role of dysfunctional Kv channels in the development of pulmonary vascular remodeling in patients with idiopathic pulmonary arterial hypertension (IPAH). Decreased K+ channel function and expression not only stimulate pulmonary artery smooth muscle cells (PASMC) proliferation by increasing [Ca2+]cyt, but also inhibits PASMC apoptosis by attenuating apoptotic volume decrease (AVD) and decreasing cytoplasmic caspase activity. The increased proliferation and inhibited apoptosis in PASMC may play an important role in initiation and/or progression of pulmonary vascular remodeling. VDCC, voltage‐dependent Ca2+ channels.

Figure 23. Figure 23.

Bone morphogenetic proteins (BMP) enhance whole‐cell Kv currents (IK(V)) in pulmonary artery smooth muscle cells (PASMC). (A) Schematic diagram depicting the proposed role of BMP‐mediated regulation of Kv channel expression and function in human PASMC. There are two types of BMP receptors (BMP‐RI and BMP‐RII) which dimerize with one another and form a BMP ligand‐receptor complex. The activated BMP‐RI phosphorylates and activates the receptor‐activated Smads (R‐Smad) which then form dimerized complexes with Co‐Smads and enter the nucleus. The R‐Smad/co‐Smad interact with DNA in the nucleus and regulate the transcription of various target genes whose primers contain the Smad binding sequence (5′‐AGAC‐3′). In the nucleus, Smad‐1 (a R‐Smad) and Smad‐4 (a co‐Smad) in association with different corepressors appear to be involved in downregulating the expression of Bcl‐2, an antiapoptotic protein that blocks the release of cytochrome c from the mitochondrial intermembrane space to the cytosol. Bcl‐2 also downregulates the mRNA expression and inhibits the function of sarcolemmal K+ channels in PASMC. (B) Representative Kv currents (left panels), following 300 ms step depolarization at potentials ranging between −60 and +80 mV from a holding potential of −70 mV, and summarized current‐voltage (I‐V) curves (right panel) in PASMC treated with (BMP‐2) or without (Control) 200 nM BMP‐2 for 24 h. (C) Representative single‐channel K+ currents in control and BMP‐2‐treated PASMC (left panels). Bar graph depicts averaged open‐state probability (NPo) of single‐channel K+ currents at +60 mV in control and BMP‐2‐treated PASMC. **P < 0.01 versus Control.

Figure 24. Figure 24.

Voltage‐dependent and ‐independent regulation of [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMC). Decreased Kv channel activity causes membrane depolarization which subsequently opens voltage‐dependent Ca2+ channels (VDCC), increases Ca2+ influx, and raises [Ca2+]cyt. Upon activation of membrane receptors including G protein‐coupled receptors (GPCR) and receptor tyrosine kinases (RTK) by ligands, store‐operated Ca2+ channels (SOC) are activated by store depletion as a result of IP3‐mediated Ca2+ mobilization from the sarcoplasmic reticulum (SR), while receptor‐operated Ca2+ channels (ROC) are activated by diacylglycerol (DAG). Increased [Ca2+]cyt is a major trigger for PASMC contraction, proliferation and migration.

Figure 25. Figure 25.

Pathogenic role of transient receptor potential channel 6 (TRPC6) in the development of idiopathic pulmonary arterial hypertension (IPAH). (A) Proposed cellular mechanisms involved in excessive increase in [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMC) isolated from patients with IPAH. Upregulated TRPC subunits (e.g., TRPC3/6), due to genetic mutations and/or environmental stimulation, lead to the increased number of receptor‐operated (ROC) and store‐operated (SOC) Ca2+ channels in the plasma membrane, which enhances receptor‐operated (ROCE) and store‐operated (SOCE) Ca2+ entry and increases [Ca2+]cyt in PASMC. Opening of SOC and ROC, potentially formed by TRPC subunits, not only causes Ca2+ influx, but also Na+ influx. The increased cytoplasmic [Na+] in the close proximity to Na+/Ca2+ exchangers (NCX) activates the reverse mode of NCX and promotes inward Ca2+ transport. NCX1 is also upregulated in IPAH PASMC in comparison to normal PASMC. (B) and (C) Representative currents (B), elicited by a ramp depolarization from −100 to +100 mV, and [Ca2+]cyt (C) before and during application of the membrane permeable diacylglycerol analogue, 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG), in PASMC from normal subjects and IPAH patients.



Figure 1.

Pulmonary angiogram (left) and cast (right) of a segment of arterial tree in human lung (A), and the proposed three schemes describing this complex structure by the Weibel model (B), the Strahler model (C), and the diameter‐defined Strahler's system (D).



Figure 2.

Electric circuit of model cell membrane and intracellular ion homeostasis. Single‐section (A) and parallel‐conductance (B) model of cell membrane. For the parallel‐conductance model, one assumes independent conductance channels for K+, Na+, and Cl. (C) Schematic diagram showing major ion channels and transporters that determine membrane potential as well as electrical and chemical gradients for K+, Na+, Ca2+, and Cl in pulmonary artery smooth muscle cells (PASMC). Resting membrane potential (Em) for a PASMC is −40 to −60 mV. EK, ENa, ECa, and ECl represent the equilibrium potentials for K+, Na+, Ca2+, and Cl, respectively. The size of the arrows indicates the driving force for the given ions. Inset, a diagram showing the channel protein embedded in the lipid membrane.



Figure 3.

Regulation of intracellular [Ca2+] (A) and the major causes of membrane depolarization (B) in pulmonary artery smooth muscle cells. SERCA, Ca2+‐Mg2+ ATPase (Ca2+ pump) in the SR/ER membrane; PM, Ca2+‐Mg2+ ATPase (Ca2+ pump) in the plasma membrane; NCX, Na+‐Ca2+ exchanger; RyR, ryanodine receptor; IP3R, inositol 1,4,5‐trisphosphate (IP3) receptor; Em, membrane potential.



Figure 4.

Topological structure of the Kv channel α‐subunit (A) and voltage‐dependent Ca2+ channels (VDCC) (B). (A) A planar representation of a Kv channel α‐subunit (a) and its interaction with other α‐subunits (b) and the β‐subunits (c) via the N‐terminal T1 domain. The graphs in b and c show a 4α‐tetramer and an 4α/4β‐octamers, respectively. The pore of the 4α‐tetramer is shown in b. (B) A planar representation of a VDCC subunit. Inset: diagrammatical representation of a VDCC channel in the plasma membrane with associated subunits. The pore region (P) forming between the S5 and S6 subunits is indicated in red.



Figure 5.

A rise in [Ca2+]cyt is a major trigger for pulmonary vasoconstriction. When [Ca2+]cyt rises in pulmonary artery smooth muscle cells, Ca2+ binds to calmodulin (CaM), which causes contraction by activating (or phosphorylating) myosin light chain kinase (MLCK) and indirectly causes the inhibition of myosin light chain phosphatase (MLCP) via Rho kinase (ROK). Activation of G protein‐coupled receptors (GPCR) can also cause Ca2+‐independent contraction (or Ca2+ sensitization) through the RhoA/ROK pathway.



Figure 6.

A rise in [Ca2+]cyt is an important stimulus of pulmonary artery smooth muscle cells proliferation. In addition to activating MLCK and causing contraction, cytosolic Ca2+ also activates CaM kinase (CaMK) and mitogen‐activated protein kinase (MAPK), as well as various transcription factors (e.g., NFAT, CREB, AP‐1 family members, and NF‐κB), to facilitate cell passage through the cell cycle and cause cell proliferation. The arrows in the inset indicate the Ca/CaM‐sensitive steps in the cell cycle. MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; PVR, pulmonary vascular resistance; PAP, pulmonary arterial pressure; SR/ER, sarcoplasmic (or endoplasmic) reticulum.



Figure 7.

Structure of transient receptor potential channel (TRPC). (A) Planar views of the TRPC1, TRPV1, and TRPM1 channel subunits. (B) Representative traces reflecting changes in [Ca2+]cyt (left panel) recorded in pulmonary artery smooth muscle cells (PASMC) before and during application of 10 μM cyclopiazonic acid (CPA), a SERCA inhibitor that depletes intracellular Ca2+ stores. 0 Ca2+, Ca2+‐free solution. The rise in [Ca2+]cyt due to store‐operated Ca2+ entry (SOCE) or capacitative Ca2+ entry (CCE) is indicated in the shadow area. The right panel shows representative whole‐cell currents recorded in human PASMC cells before (−CPA) and after (+CPA) depletion of intracelluarly stored Ca2+ from the SR using 10 μM CPA.



Figure 8.

Oligomerization and translocation of STIM to SR/ER‐plasma membrane junctions are the major mechanism involved in SOCE through Orai tetramer‐formed SOC. (A) The Ca2+ sensor EF‐hand domain in the N terminus of STIM has bound Ca2+ (red circles) when the SR/ER Ca2+ store is filled with Ca2+ (up to 1 mM). Depletion of Ca2+ from the SR/ER causes Ca2+ to unbind from the low‐affinity EF‐hand of STIM, which subsequently leads to STIM oligomerization and translocation to the SR/ER‐plasma membrane junctions. (B) STIM accumulation in the vicinity of Orai channel dimmers induces Orai channels to cluster in the adjacent plasma membrane. The C‐terminal effector domain of STIM causes Orai channels to open by direct binding of the distal coiled‐coil domain, and triggers Ca2+ entry. Two STIMs can activate a single SOC formed by an Orai tetramer; channel activation of Orai may involve a preliminary step of assembling Orai dimmers into a functional tetramer.



Figure 9.

Functional coupling of receptors,  transient receptor potential channel (TRPC) and NCX in caveolae in pulmonary artery smooth muscle cells (PASMC). (A) Electron microscopy graphs showing the structure of plasma membrane in PASMC isolated from normal subjects and patients with idiopathic pulmonary arterial hypertension (IPAH). IPAH PASMC have increased flask‐like invaginations of the plasma membrane consistent with the morphology of caveolae (indicated by arrows) and as determined by the number of caveoli per membrane length. (B) and (C) Schematic diagram depicting the caveolin‐1 binding domains of TRPC1 (B) and the potential mechanisms (C) that are involved in ligand‐mediated regulation of intracellular [Ca2+]cyt through G protein‐coupled receptors (GPCR), TRPC, and Na+/Ca2+ exchangers (NCX) in caveolae. CBM, cav1‐binding motif; PBD, protein 4‐binding domain; CSD, caveolin‐scaffolding domain; PM, the plasma membrane; ER/SR, endoplasmic reticulum and sarcoplasmic reticulum; G, G protein; IP3, inositol 1,4,5‐trisphosphate; IP3R, IP3 receptor; SERCA, SR/ER Ca2+‐Mg2+ ATPase; Cav‐1, caveolin‐1.



Figure 10.

Structure of K+ channels. Planar membrane topologies of single K+ channel subunits for voltage‐gated K+ (Kv) channels (A), Ca2+‐activated (BKCa) K+ channels (B), inward rectifier K+ (KIR) channels (C), and two‐pore domain (K2P) K+ channels (D), respectively. The pore‐forming loop is indicated and the voltage sensor in the transmembrane (TM) domain 4 for Kv and BKCa channels. Membrane topology of a K2P channel subunit featuring two pore regions, P1 and P2 and four TM‐spanning domains, M1 to 4 and cytoplasmic N‐ and C‐ termini (D). The ATP‐sensitive K+ (KATP) channels are heterooctamers formed by the pore‐forming KIR subunits and the regulatory subunits, SUR (e.g., Kir6.1/SUR2B and Kir6.2/SUR2B) (as shown in C).



Figure 11.

Structure of voltage‐gated Na+ channels. (A) Planar schematic diagram showing structural arrangement of Na+ channel α and β12 subunits. (B) Representative currents showing inward Na+ currents (INa) in human pulmonary artery smooth muscle cells (PASMC), elicited by depolarizing the cell from a holding potential of −70 mV to a series of test potentials ranging from −80 and +80 mV in 20 mV increments. The inset indicates the summarized I‐V relationship curve for INa. (C) Representative INa at 0 mV from PASMC before, during and after extracellular application of 1 μM tetrodotoxin.



Figure 12.

Ca2+‐activated Cl currents (IClCa) in pulmonary artery smooth muscle cells (PASMC). (A) A representative family of whole‐cell IClCa in PASMC elicited by a series of test potentials from −60 to +60 mV in 20‐mV increments (from a holding potential of −70 mV). The cells are superfused with Modified Kreb's solution (MKS) including 1.8 mM Ca2+. (B) Representative traces of IClCa recorded in PASMC superfused with MKS (Control and Recovery) and Ca2+‐free MKS with 10 mM BaCl2 (0Ca‐10Ba). Replacement of extracellular Ca2+ with Ba2+ significantly enhanced inward cation current, but abolished the outward Cl currents and the inward tail currents, which were carried by Cl influx and efflux, respectively, through ClCa channels. (C) The superimposed record of whole‐cell IClCa in PASMC before (Control) and during extracellular application of niflumic acid.



Figure 13.

Gap junction (GJ) and GJ channels in vascular smooth muscle and endothelial cells. The changes in membrane potential (Em) and [Ca2+]cyt due to Ca2+ influx or release in one smooth muscle cell (SMC) can be communicated to an adjacent SMC through GJ channels and to an endothelial cell (EC) through GJ channels in the myoendothelial junction (MEJ). Ca2+ and electrical signals can also go through GJ channels between ECs. In addition to Ca2+ and other cations/anions, GJ channels also allow small molecules to go through, for example, IP3, DAG, and other second messengers in the cytosol. ER, endoplasmic reticulum; SR, sarcoplasmic reticulum; δEm, changes in Em (i.e., membrane depolarization, hyperpolarization, or repolarization); ROC, receptor‐operated Ca2+ channels.



Figure 14.

Formation of gap junction (GJ) channels and topology of the connexin (Cx). (A) A schematic diagram showing how the hemichannels in the membrane of one cell interact with the hemichannels in another cell to form GJ channels. Not all hemichannels form GJ channels; the hemichannels can also function as a non‐selective cation/anion channels. (B) The Cx is a membrane protein with four transmembrane domains and cytoplasmic N‐ and C‐termini. There are multiple cysteine residues in the extracellular E1 and E2 segments that make the channel sensitive to the regulation of oxidation and reduction.



Figure 15.

Inhibition of K+ channels causes membrane depolarization and causes pulmonary vasoconstriction. (A) Close of K+ channels in pulmonary artery smooth muscle cells (PASMC) causes membrane depolarization, which subsequently opens VDCC, enhances Ca2+ influx, increases [Ca2+]cyt, and induces pulmonary vasoconstriction. Opening of K+ channels, on the other hand, causes membrane hyperpolarization (close to the K+ equilibrium potential), decreases VDCC activity and causes pulmonary vasodilation. (B) Representative records of whole‐cell K+ currents (a), membrane potential (Em, b) and [Ca2+]cyt (c) in PASMC before (control), during (4‐AP) and after (wash) extracellular application of 5 mM 4‐amynopyridine (4‐AP). A representative record of tension measurement in an isolated pulmonary arterial ring before, during, and after 4‐AP treatment is shown in d.



Figure 16.

Activity of K+ channel is involved in apoptotic volume decrease (AVD) and apoptosis. (A) Diagram showing the chronological order of morphological and biochemical changes during apoptotic stimulation. Activation of K+ channels leads to a loss of intracellular K+, which relieves the inhibitory effect of K+ on cytoplasmic caspases and nucleases, increases caspase‐mediated cleavage, and ultimately induces nuclear breakage and apoptosis. Activation of K+ channels also accelerates AVD, which further facilitates the process leading to apoptosis. (B) Changes in cell morphology before (Control) and during treatment with apoptosis inducers. Exposure of cells to pro‐apoptotic triggers activates K+ (and Cl) channels, induces AVD, and ultimately causes DNA fragmentation and nuclear breakage. The image on the right showing DAPI‐stained nuclei in pulmonary artery smooth muscle cells treated with staurosporine; the cells undergoing apoptosis (showing significant nuclear breakage) are indicated by arrows. The AVD due to K+ (Cl and H2O) efflux occurs prior to nuclear condensation and DNA fragmentation.



Figure 17.

Two pathways of apoptosis. When death receptors (DR) are activated (e.g., by Fas ligand), cleavage of procaspase 8 (and/or 10) to active caspase 8 is an important initial step to induce apoptosis. Cytochrome c (Cyt c), which can be released from the mitochondria to the cytosol when cells are exposed to UV light or when mitochondrial membrane potential (δΨm) is depolarized, activates cytoplasmic caspase 9. Active caspases 8 and 9 then activate caspases 3/6/7 and cause DNA fragmentation and nuclear breakage, and eventually cell death. Cytosolic cytochrome c also activates Kv channels, induces K+ loss, decreases cytosolic [K+], which increases caspase activity and accelerates AVD, and ultimately promote apoptosis .



Figure 18.

Cellular mechanisms by which acute hypoxia causes pulmonary vasoconstriction. (A) Multiple pathways are involved in hypoxia‐induced increase in [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMC). Acute hypoxia can enhance Ca2+ influx through receptor‐operated Ca2+ channels (ROC) by activating phospholipase C (PLC) and diacylglycerol (DAG), through voltage‐dependent Ca2+ channels (VDCC) by membrane depolarization due to inhibition of K+ (Kv and K2P) channels and activation of Ca2+‐activated Cl (ClCa) channels, and through store‐operated Ca2+ channels (SOC) by active depletion of Ca2+ from the SR/ER. Acute hypoxia can also enhance Ca2+ release from the SR/ER, lysosome and mitochondrial by activating IP3 receptors (IP3R) and ryanodine (RyR) receptors, producing pyridine nucleotides (cyclic adenosine diphosphate‐ribose, cADPR and nicotinic acid adenine dinucleotide phosphate, NAADP), and inhibiting electron transportation chain (ETC), respectively. Store depletion may also increase Na+ influx through SOC and increases cytosolic [Na+], which would subsequently stimulate inward Ca2+ transportation via the reverse mode of Na+/Ca2+ exchange (NCX). (B) Representative records of whole‐cell Kv currents (IK(V)), membrane potential (Em), and [Ca2+]cyt in PASMC before (normoxia), during (hypoxia) and after (recovery) exposure to hypoxia. (C) Acute hypoxia decreases IK(V) only in KCNA5‐transfected PASMC, but not in mesenteric artery smooth muscle cells (MASMC) transfected with KCNA5 gene.



Figure 19.

Cellular mechanisms by which chronic hypoxia causes pulmonary vascular remodeling and vasoconstriction. Chronic exposure to hypoxia downregulates Kv and K2P channels and upregulates Ca2+‐activated Cl (ClCa) channels in pulmonary artery smooth muscle cells (PASMC). The resultant membrane depolarization opens voltage‐dependent Ca2+ channels (VDCC) and increases [Ca2+]cyt. Chronic hypoxia also upregulates VDCC (α1C), transient receptor potential channel (TRPC1/3/4/6), and Orai2/STIM2 proteins in PASMC. The resultant augmentation of Ca2+ influx through these upregulated Ca2+ channels further increase [Ca2+]cyt and ultimately causes pulmonary vasoconstriction and vascular remodeling. Downregulation of K+ channels also contributes to pulmonary vascular remodeling by inhibiting AVD and apoptosis in PASMC.



Figure 20.

Schematic diagram showing the causes of elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH, A) and the angiographic and histological features of the pulmonary vasculature in IPAH patients (B). The angiogram show significant “loss” of small vessels in the IPAH patient (B, upper panels), which is mainly due to sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling characterized by medial and intimal hypertrophy, neointimal proliferation, and obliteration of small pulmonary arteries and arterioles (B, lower panels). EVG, elastic Van Gieson staining.

The images shown in B are reproduced from Ref. 1957.


Figure 21.

Patterns of vascular remodeling (A) and common histological changes in the pulmonary vasculature in patients with pulmonary hypertension (B). (A) The remodeling of a vessel to a larger lumen with the same wall thickness is termed “outward hypertrophic” (or eccentric hypertrophy), since cross‐sectional area is increased. Conversely, vessel narrowing with increased wall thickness occurs in chronic hypertension and may be “inward eutrophic” (e.g., smaller lumen with a somewhat thicker wall, but the same cross‐sectional area) or “inward hypertrophic” or “concentric hypertrophy” (i.e., smaller lumen with sufficient wall thickening to increase cross‐sectional area). A common assumption is that changes in cross‐sectional area indicate changes in wall mass (as implied by the terms “hypotrophic” or hypertrophic”). This, of course, is only correct if vessel length is not altered . (B) In the lung, pulmonary vascular remodeling consists in concentric hypertrophy, eccentric hypertrophy (associated with adventitial lesion and hypertrophy and extracellular matrix lesions), and obliteration of small vessels due to intimal lesions, plexiform lesions and in situ thrombosis. Concentric hypertrophy, in situ thrombosis and obliteration increase pulmonary vascular resistance (PVR) by narrowing the affected arterial lumen, while eccentric hypertrophy contributes to increasing PVR by increasing the wall stiffness or decreasing the vascular wall compliance (which is one of the major causes for reduced distention and recruitment in pulmonary circulation).



Figure 22.

Schematic diagram showing the pathogenic role of dysfunctional Kv channels in the development of pulmonary vascular remodeling in patients with idiopathic pulmonary arterial hypertension (IPAH). Decreased K+ channel function and expression not only stimulate pulmonary artery smooth muscle cells (PASMC) proliferation by increasing [Ca2+]cyt, but also inhibits PASMC apoptosis by attenuating apoptotic volume decrease (AVD) and decreasing cytoplasmic caspase activity. The increased proliferation and inhibited apoptosis in PASMC may play an important role in initiation and/or progression of pulmonary vascular remodeling. VDCC, voltage‐dependent Ca2+ channels.



Figure 23.

Bone morphogenetic proteins (BMP) enhance whole‐cell Kv currents (IK(V)) in pulmonary artery smooth muscle cells (PASMC). (A) Schematic diagram depicting the proposed role of BMP‐mediated regulation of Kv channel expression and function in human PASMC. There are two types of BMP receptors (BMP‐RI and BMP‐RII) which dimerize with one another and form a BMP ligand‐receptor complex. The activated BMP‐RI phosphorylates and activates the receptor‐activated Smads (R‐Smad) which then form dimerized complexes with Co‐Smads and enter the nucleus. The R‐Smad/co‐Smad interact with DNA in the nucleus and regulate the transcription of various target genes whose primers contain the Smad binding sequence (5′‐AGAC‐3′). In the nucleus, Smad‐1 (a R‐Smad) and Smad‐4 (a co‐Smad) in association with different corepressors appear to be involved in downregulating the expression of Bcl‐2, an antiapoptotic protein that blocks the release of cytochrome c from the mitochondrial intermembrane space to the cytosol. Bcl‐2 also downregulates the mRNA expression and inhibits the function of sarcolemmal K+ channels in PASMC. (B) Representative Kv currents (left panels), following 300 ms step depolarization at potentials ranging between −60 and +80 mV from a holding potential of −70 mV, and summarized current‐voltage (I‐V) curves (right panel) in PASMC treated with (BMP‐2) or without (Control) 200 nM BMP‐2 for 24 h. (C) Representative single‐channel K+ currents in control and BMP‐2‐treated PASMC (left panels). Bar graph depicts averaged open‐state probability (NPo) of single‐channel K+ currents at +60 mV in control and BMP‐2‐treated PASMC. **P < 0.01 versus Control.



Figure 24.

Voltage‐dependent and ‐independent regulation of [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMC). Decreased Kv channel activity causes membrane depolarization which subsequently opens voltage‐dependent Ca2+ channels (VDCC), increases Ca2+ influx, and raises [Ca2+]cyt. Upon activation of membrane receptors including G protein‐coupled receptors (GPCR) and receptor tyrosine kinases (RTK) by ligands, store‐operated Ca2+ channels (SOC) are activated by store depletion as a result of IP3‐mediated Ca2+ mobilization from the sarcoplasmic reticulum (SR), while receptor‐operated Ca2+ channels (ROC) are activated by diacylglycerol (DAG). Increased [Ca2+]cyt is a major trigger for PASMC contraction, proliferation and migration.



Figure 25.

Pathogenic role of transient receptor potential channel 6 (TRPC6) in the development of idiopathic pulmonary arterial hypertension (IPAH). (A) Proposed cellular mechanisms involved in excessive increase in [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMC) isolated from patients with IPAH. Upregulated TRPC subunits (e.g., TRPC3/6), due to genetic mutations and/or environmental stimulation, lead to the increased number of receptor‐operated (ROC) and store‐operated (SOC) Ca2+ channels in the plasma membrane, which enhances receptor‐operated (ROCE) and store‐operated (SOCE) Ca2+ entry and increases [Ca2+]cyt in PASMC. Opening of SOC and ROC, potentially formed by TRPC subunits, not only causes Ca2+ influx, but also Na+ influx. The increased cytoplasmic [Na+] in the close proximity to Na+/Ca2+ exchangers (NCX) activates the reverse mode of NCX and promotes inward Ca2+ transport. NCX1 is also upregulated in IPAH PASMC in comparison to normal PASMC. (B) and (C) Representative currents (B), elicited by a ramp depolarization from −100 to +100 mV, and [Ca2+]cyt (C) before and during application of the membrane permeable diacylglycerol analogue, 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG), in PASMC from normal subjects and IPAH patients.

References
 1. Aaronson PI, Robertson TP, Knock GA, Becker S, Lewis TH, Snetkov V, Ward JP. Hypoxic pulmonary vasoconstriction: Mechanisms and controversies. J Physiol 570: 53‐58, 2006.
 2. Abdel‐Ghany M, Cheng HC, Elble RC, Lin H, DiBiasio J, Pauli BU. The interacting binding domains of the β4 integrin and calcium‐activated chloride channels (CLCAs) in metastasis. J Biol Chem 278: 49406‐49416, 2003.
 3. Accili EA, Kiehn J, Wible BA, Brown AM. Interactions among inactivating and noninactivating Kvβ subunits, and Kvα1.2, produce potassium currents with intermediate inactivation. J Biol Chem 272: 28232‐28236, 1997.
 4. Accili EA, Kiehn J, Yang Q, Wang Z, Brown AM, Wible BA. Separable Kvβ subunit domains alter expression and gating of potassium channels. J Biol Chem 272: 25824‐25831, 1997.
 5. Aggarwal SK, MacKinnon R. Contribution of the S4 segment to gating charge in the Shaker K+ channel. Neuron 16: 1169‐1177, 1996.
 6. Aguilar‐Bryan L, Nichols CG, Wechsler SW, Clement JP, Boyd AE, González G, Herrera‐Sosa H, Nguy K, Bryan J, Nelson DA. Cloning of the β cell high‐affinity sulfonylurea receptor: A regulator of insulin secretion. Science 268: 423‐426, 1995.
 7. Alfranca A, Gutierrez MD, Vara A, Aragones J, Vidal F, Landazuri MO. c‐Jun and hypoxia‐inducible factor 1 functionally cooperate in hypoxia‐induced gene transcription. Mol Cell Biol 22: 12‐22, 2002.
 8. Alioua A, Tanaka Y, Wallner M, Hofmann F, Ruth P, Meera P, Toro L. The large‐conductance, voltage‐dependent, and calcium‐sensitive K+ channel, Hslo, is a target of cGMP‐dependent protein kinase phosphorylation in vivo. J Biol Chem 273: 32950‐32956, 1998.
 9. Alldredge B. Clinical connexions. J Clin Pathol 61: 885‐890, 2008.
 10. Archer SL, Gomberg‐Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK. Mitochondrial metabolism, redox signaling, and fusion: A mitochondria‐ROS‐HIF‐1α‐Kv1.5 O2‐sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 294: H570‐H578, 2008.
 11. Archer SL, Huang J, Henry T, Peterson D, Weir EK. A redox‐based O2 sensor in rat pulmonary vasculature. Circ Res 73: 1100‐1112, 1993.
 12. Archer SL, Reeve HL, Michelakis E, Puttagunta L, Waite R, Nelson DP, Dinauer MC, Weir EK. O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase. Proc Natl Acad Sci U S A 96: 7944‐7949, 1999.
 13. Archer SL, Souil E, Dinh‐Xuan AT, Schremmer B, Mercier JC, El Yaagoubi A, Nguyen‐Huu L, Reeve HL, Hampl V. Molecular identification of the role of voltage‐gated K+ channels, Kv1.5 and Kv1.2, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. J Clin Invest 101: 2319‐2330, 1998.
 14. Archer SL, Weir EK, Reeve HL, Michelakis E. Molecular identification of O2 sensors and O2‐sensitive potassium channels in the pulmonary circulation. Adv Exp Med Biol 475: 219‐240, 2000.
 15. Aung CS, Kruger WA, Poronnik P, Roberts‐Thomson SJ, Monteith GR. Plasma membrane Ca2+‐ATPase expression during colon cancer cell line differentiation. Biochem Biophys Res Commun 355: 932‐936, 2007.
 16. Bai C, Fukuda N, Song Y, Ma T, Matthay MA, Verkman AS. Lung fluid transport in aquaporin‐1 and aquaporin‐4 knockout mice. J Clin Invest 103: 555‐561, 1999.
 17. Barman SA, Zhu S, White RE. PKC activates BKCa channels in rat pulmonary arterial smooth muscle via cGMP‐dependent protein kinase. Am J Physiol Lung Cell Mol Physiol 286: L1275‐L1281, 2004.
 18. Barst RJ. Recent advances in the treatment of pediatric pulmonary artery hypertension. Pediatr Clin North Am 46: 331‐345, 1999.
 19. Beasley D, Cohen RA, Levinsky NG. Interleukin 1 inhibits contraction of vascular smooth muscle. J Clin Invest 83: 331‐335, 1989.
 20. Beech DJ. Emerging functions of 10 types of TRP cationic channel in vascular smooth muscle. Clin Exp Pharmacol Physiol 32: 597‐603, 2005.
 21. Beech DJ. Ions in smooth muscle, now and then. J Physiol 570: 3, 2006.
 22. Beech DJ, Xu SZ, McHugh D, Flemming R. TRPC1 store‐operated cationic channel subunit. Cell Calcium 33: 433‐440, 2003.
 23. Beech DJ, Zhang H, Nakao K, Bolton TB. K‐channel activation by nucleotide diphosphates and its inhibition by glibenclamide in vascular smooth muscle cells. Br J Pharmacol 110: 573‐582, 1993.
 24. Bergdahl A, Gomez MF, Dreja K, Xu SZ, Adner M, Beech DJ, Broman J, Hellstrand P, Sward K. Cholesterol depletion impairs vascular reactivity to endothelin‐1 by reducing store‐operated Ca2+ entry dependent on TRPC1. Circ Res 93: 839‐847, 2003.
 25. Berk B. Vascular smooth muscle growth: Autocrine growth mechanisms. Physiol Rev 81: 999‐1030, 2001.
 26. Berridge MJ. Calcium signalling and cell proliferation. BioEssays 17: 491‐500, 1995.
 27. Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: Dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4: 517‐529, 2003.
 28. Bkaily G, Naik R, Jaalouk D, Jacques D, Economos D, D'Orleans‐Juste P, Pothier P. Endothelin‐1 and insulin activate the steady‐state voltage‐dependent R‐type Ca2+ channel in aortic smooth muscle cells via a pertussis toxin and cholera toxin sensitive G‐protein. Mol Cell Biochem 183: 39‐47, 1998.
 29. Blanco G, Sanchez G, Mercer RW. Differential regulation of Na,K‐ATPase isozymes by protein kinases and arachidonic acid. Arch Biochem Biophys 359: 139‐150, 1998.
 30. Blaustein MP, Lederer WJ. Sodium/calcium exchange: Its physiological implications. Physiol Rev 79: 763‐854, 1999.
 31. Blaustein MP, Zhang J, Chen L, Hamilton BP. How does salt retention raise blood pressure? Am J Physiol Regul Integr Comp Physiol 290: R514‐R523, 2006.
 32. Bock J, Szabó I, Jekle A, Gulbins E. Actinomycin D‐induced apoptosis involves the potassium channel Kv1.3. Biochem Biophys Res Comm 295: 526‐531, 2002.
 33. Bonnet S, Archer SL, Allalunis‐Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria‐K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11: 37‐51, 2007.
 34. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, Hashimoto K, Bonnet SN, Michelakis ED. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci U S A 104: 11418‐11423, 2007.
 35. Bortner CD, Cidlowski JA. Absence of volume regulatory mechanisms contributes to the rapid activation of apoptosis in thymocytes. Am J Physiol 271: C950‐C961, 1996.
 36. Bortner CD, Cidlowski JA. Caspase independent/dependent regulation of K+, cell shrinkage, and mitochondrial membrane potential during lymphocyte apoptosis. J Biol Chem 274: 21953‐21962, 1999.
 37. Bortner CD, Cidlowski JA. Volume regulation and ion transport during apoptosis. Methods Enzymol 322: 421‐433, 2000.
 38. Bortner CD, Hughes FM Jr, Cidlowski JA. A primary role for K+ and Na+ efflux in the activation of apoptosis. J Biol Chem 272: 32436‐32442, 1997.
 39. Braun A, Varga‐Szabo D, Kleinschnitz C, Pleines I, Bender M, Austinat M, Bosl M, Stoll G, Nieswandt B. Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation. Blood 113: 2056‐2063, 2009.
 40. Brayden JE, Nelson MT. Regulation of arterial tone by activation of calcium‐dependent potassium channels. Science 256: 532‐535, 1992.
 41. Brevnova EE, Platoshyn O, Zhang S, Yuan JX. Overexpression of human KCNA5 increases IK(V) and enhances apoptosis. Am J Physiol Cell Physiol 287: C715‐C722, 2004.
 42. Burg ED, Platoshyn O, Tsigelny IF, Lozano‐Ruiz B, Rana BK, Yuan JX. Tetramerization domain mutations in KCNA5 affect channel kinetics and cause abnormal trafficking patterns. Am J Physiol Cell Physiol 298: C496‐C509.
 43. Burrowes KS, Hunter PJ, Tawhai MH. Anatomically based finite element models of the human pulmonary arterial and venous trees including supernumerary vessels. J Appl Physiol 99: 731‐738, 2005a.
 44. Burrowes KS, Hunter PJ, Tawhai MH. Investigation of the relative effects of vascular branching structure and gravity on pulmonary arterial blood flow heterogeneity via an image‐based computational model. Acad Radiol 12: 1464‐1474, 2005b.
 45. Burrowes KS, Tawhai MH. Computational predictions of pulmonary blood flow gradients: Gravity versus structure. Respir Physiol Neurobiol 154: 515‐523, 2006.
 46. Cahalan MD. STIMulating store‐operated Ca2+ entry. Nat Cell Biol 11: 669‐677, 2009.
 47. Cain K, Langlais C, Sung X‐M, Brown DG, Cohen GM. Physiological concentrations of K+ inhibit cytochrome c‐dependent formation of the apoptosome. J Biol Chem 276: 41985‐41990, 2001.
 48. Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, Chuang KT, Lin P, Xiao R, Wang C, Zhu Y, Lin Y, Wyatt CN, Parrington J, Ma J, Evans AM, Galione A, Zhu MX. NAADP mobilizes calcium from acidic organelles through two‐pore channels. Nature 459: 596‐600, 2009.
 49. Campbell WB, Gebremedhin D, Pratt PF, Harder DR. Identification of epoxyeicosatrienoic acids as endothelium‐derived hyperpolarizing factors. Circ Res 78: 415‐423, 1996.
 50. Capozza F, Combs TP, Cohen AW, Cho YR, Park SY, Schubert W, Williams TM, Brasaemle DL, Jelicks LA, Scherer PE, Kim JK, Lisanti MP. Caveolin‐3 knockout mice show increased adiposity and whole body insulin resistance, with ligand‐induced insulin receptor instability in skeletal muscle. Am J Physiol Cell Physiol 288: C1317‐C1331, 2005.
 51. Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra‐Moran O, Galietta LJ. TMEM16A, a membrane protein associated with calcium‐dependent chloride channel activity. Science 322: 590‐594, 2008.
 52. Carter EP, Olveczky BP, Matthay MA, Verkman AS. High microvascular endothelial water permeability in mouse lung measured by a pleural surface fluorescence method. Biophys J 74: 2121‐2128, 1998.
 53. Catterall WA. Structure and regulation of voltage‐gated Ca2+ channels. Annu Rev Cell Dev Biol 16: 521‐555, 2000.
 54. Catterall WA, Perez‐Reyes E, Snutch TP, Striessnig J. International Union of Pharmacology. XLVIII. Nomenclature and structure‐function relationships of voltage‐gated calcium channels. Pharmacol Rev 57: 411‐425, 2005.
 55. Chanda D, Krishna AV, Gupta PK, Singh TU, Prakash VR, Sharma B, Joshi P, Mishra SK. Role of low ouabain‐sensitive isoform of Na+‐K+‐ATPase in the regulation of basal tone and agonist‐induced contractility in ovine pulmonary artery. J Cardiovasc Pharmacol 52: 167‐175, 2008.
 56. Chaytor AT, Bakker LM, Edwards DH, Griffith TM. Connexin‐mimetic peptides dissociate electrotonic EDHF‐type signalling via myoendothelial and smooth muscle gap junctions in the rabbit iliac artery. Br J Pharmacol 144: 108‐114, 2005.
 57. Chaytor AT, Edwards DH, Bakker LM, Griffith TM. Distinct hyperpolarizing and relaxant roles for gap junctions and endothelium‐derived H2O2 in NO‐independent relaxations of rabbit arteries. Proc Natl Acad Sci U S A 100: 15212‐15217, 2003.
 58. Chaytor AT, Evans WH, Griffith TM. Central role of heterocellular gap junctional communication in endothelium‐dependent relaxation of rabbit arteries. J Physiol 508: 561‐573, 1998.
 59. Chen TT, Luykenaar KD, Walsh EJ, Walsh MP, Cole WC. Key role of Kv1 channels in vasoregulation. Circ Res 99: 53‐60, 2006.
 60. Chipperfield AR, Harper AA. Chloride in smooth muscle. Prog Biophys Mol Biol 74: 175‐221, 2000.
 61. Choby C, Mangoni ME, Boccara G, Nargeot J, Richard S. Evidence for tetrodotoxin‐sensitive sodium currents in primary cultured myocytes from human, pig and rabbit arteries. Pflügers Arch 440: 149‐152, 2000.
 62. Cioffi DL, Barry C, Stevens T. Store‐operated calcium entry channels in pulmonary endothelium: The emerging story of TRPCS and Orai1. Adv Exp Med Biol 661: 137‐154, 2010.
 63. Cipolletta E, Monaco S, Maione AS, Vitiello L, Campiglia P, Pastore L, Franchini C, Novellino E, Limongelli V, Bayer KU, Means AR, Rossi G, Trimarco B, Iaccarino G, Illario M. Calmodulin‐dependent kinase II mediates vascular smooth muscle cell proliferation and is potentiated by extracellularly regulated kinase. Endocrinology 151: 2747‐2759, 2010.
 64. Clapham DE. TRP channels as cellular sensors. Nature 426: 517‐524, 2003.
 65. Cogolludo A, Moreno L, Lodi F, Frazziano G, Cobeño L, Tamargo J, Perez‐Vizcaino F. Serotonin inhibits voltage‐gated K+ currents in pulmonary artery smooth muscle cells: Role of 5‐HT2A receptors, caveolin‐1, and KV1.5 channel internalization. Circ Res 98: 931‐938, 2006.
 66. Coppock EA, Martens JR, Tamkun MM. Molecular basis of hypoxia‐induced pulmonary vasoconstriction: Role of voltage‐gated K+ channels. Am J Physiol Lung Cell Mol Physiol 281: L1‐L12, 2001.
 67. Cox RH, Rusch NJ. New expression profiles of voltage‐gated ion channels in arteries exposed to high blood pressure. Microcirculation 9: 243‐257, 2002.
 68. Cui Y, Tran S, Tinker A, Clapp LH. The molecular composition of KATP channels in human pulmonary artery smooth muscle cells and their modulation by growth. Am J Respir Cell Mol Biol 26: 135‐143, 2002.
 69. Dai Y‐P, Bongalon S, Hatton WJ, Hume JR, Yamboliev IA. ClC‐3 chloride channel is upregulated by hypertrophy and inflammation in rat and canine pulmonary artery. Br J Pharmacol 145: 5‐14, 2005.
 70. Dallaporta B, Hirsch T, Susin SA, Zamzami N, Larochette N, Brenner C, Marzo I, Kroemer G. Potassium leakage during the apoptotic degradation phase. J Immunol 160: 5605‐5615, 1998.
 71. Dietrich A, Chubanov V, Kalwa H, Rost BR, Gudermann T. Cation channels of the transient receptor potential superfamily: Their role in physiological and pathophysiological processes of smooth muscle cells. Pharmacol Ther 112: 744‐760, 2006.
 72. Drummond HA, Gebremedhin D, Harder DR. Degenerin/epithelial Na+ channel proteins: Components of a vascular mechanosensor. Hypertension 44: 643‐648, 2004.
 73. Drummond HA, Grifoni SC, Jernigan NL. A new trick for an old dogma: ENaC proteins as mechanotransducers in vascular smooth muscle. Physiology (Bethesda) 23: 23‐31, 2008.
 74. Dumitrascu R, Weissmann N, Ghofrani HA, Dony E, Beuerlein K, Schmidt H, Stasch J‐P, Gnoth MJ, Seeger W, Grimminger F, Schermuly RT. Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling. Circulation 113: 286‐295, 2006.
 75. Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C, Lazdunski M. TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J 16: 5464‐5471, 1997.
 76. Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH. K+ is an endothelium‐derived hyperpolarizing factor in rat arteries. Nature 396: 269‐272, 1998.
 77. Ekhterae D, Platoshyn O, Krick S, Yu Y, McDaniel SS, Yuan JX. Bcl‐2 decreases voltage‐gated K+ channel activity and enhances survival in vascular smooth muscle cells. Am J Physiol Cell Physiol 281: C157‐C165, 2001.
 78. Ekhterae D, Platoshyn O, Zhang S, Remillard CV, Yuan JX. Apoptosis repressor with caspase domain inhibits cardiomyocyte apoptosis by reducing voltage‐gated K+ currents. Am J Physiol Cell Physiol 284: C1405‐C1410, 2003.
 79. Engelman JA, Chu C, Lin A, Jo H, Ikezu T, Okamoto T, Kohtz DS, Lisanti MP. Caveolin‐mediated regulation of signaling along the p42/44 MAP kinase cascade in vivo. A role for the caveolin‐scaffolding domain. FEBS Lett 428: 205‐211, 1998.
 80. Engelman JA, Lee RJ, Karnezis A, Bearss DJ, Webster M, Siegel P, Muller WJ, Windle JJ, Pestell RG, Lisanti MP. Reciprocal regulation of neu tyrosine kinase activity and caveolin‐1 protein expression in vitro and in vivo. Implications for human breast cancer. J Biol Chem 273: 20448‐20455, 1998.
 81. Engelman JA, Zhang XL, Galbiati F, Lisanti MP. Chromosomal localization, genomic organization, and developmental expression of the murine caveolin gene family (Cav‐1, ‐2, and ‐3). Cav‐1 and Cav‐2 genes map to a known tumor suppressor locus (6‐A2/7q31). FEBS Lett 429: 330‐336, 1998.
 82. Evans W, Short, DS, Bedford, DE Solitary pulmonary hypertension. Br Heart J 19: 93‐116, 1957.
 83. Evans WH, Martin PE. Gap junctions: Structure and function. Mol Membr Biol 19: 121‐136, 2002.
 84. Fantozzi I, Platoshyn O, Wong AH, Zhang S, Remillard CV, Furtado MR, Petrauskene OV, Yuan JX. Bone morphogenetic protein‐2 upregulates expression and function of voltage‐gated K+ channels in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 291: L993‐L1004, 2006.
 85. Fantozzi I, Zhang S, Platoshyn O, Remillard CV, Cowling RT, Yuan JX. Hypoxia increases AP‐1 binding activity by enhancing capacitative Ca2+ entry in human pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol 285: L1233‐L1245, 2003.
 86. Figueroa XF, Isakson BE, Duling BR. Connexins: Gaps in our knowledge of vascular function. Physiology (Bethesda) 19: 277‐284, 2004.
 87. Fike CD, Kaplowitz MR, Zhang Y, Madden JA. Voltage‐gated K+ channels at an early stage of chronic hypoxia‐induced pulmonary hypertension in newborn piglets. Am J Physiol Lung Cell Mol Physiol 291: L1169‐L1176, 2006.
 88. Firth AL, Remillard CV, Yuan JX. TRP channels in hypertension. Biochim Biophys Acta 1772: 895‐906, 2007.
 89. Firth AL, Yuill KH, Smirnov SV. Mitochondria‐dependent regulation of Kv currents in rat pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 295: L61‐L70, 2008.
 90. Fleischmann BK, Murray RK, Kotlikoff MI. Voltage window for sustained elevation of cytosolic calcium in smooth muscle cells. Proc Natl Acad Sci U S A 91: 11914‐11918, 1994.
 91. Fleming I. Cytochrome P450 enzymes in vascular homeostasis. Circ Res 89: 753‐762, 2001.
 92. Franco‐Obregon A, Lopez‐Barneo J. Differential oxygen sensitivity of calcium channels in rabbit smooth muscle cells of conduit and resistance pulmonary arteries. J Physiol 491: 511‐518, 1996.
 93. Freichel M, Suh SH, Pfeifer A, Schweig U, Trost C, Weissgerber P, Biel M, Philipp S, Freise D, Droogmans G, Hofmann F, Flockerzi V, Nilius B. Lack of an endothelial store‐operated Ca2+ current impairs agonist‐dependent vasorelaxation in TRP4−/− mice. Nat Cell Biol 3: 121‐127, 2001.
 94. Fu D, Lu M. The structural basis of water permeation and proton exclusion in aquaporins. Mol Membr Biol 24: 366‐374, 2007.
 95. Gardener MJ, Johnson IT, Burnham MP, Edwards G, Heagerty AM, Weston AH. Functional evidence of a role for two‐pore domain potassium channels in rat mesenteric and pulmonary arteries. Br J Pharmacol 142: 192‐202, 2004.
 96. Garland CJ, Plane F, Kemp BK, Cocks TM. Endothelium‐dependent hyperpolarization: A role in the control of vascular tone. Trends Pharmacol Sci 16: 23‐30, 1995.
 97. Geering K. Functional roles of Na,K‐ATPase subunits. Curr Opin Nephrol Hypertens 17: 526‐532, 2008.
 98. Ghosh B, Kar P, Mandal A, Dey K, Chakraborti T, Chakraborti S. Ca2+ influx mechanisms in caveolae vesicles of pulmonary smooth muscle plasma membrane under inhibition of alpha2beta1 isozyme of Na+/K+‐ATPase by ouabain. Life Sci 84: 139‐148, 2009.
 99. Golovina VA, Platoshyn O, Bailey CL, Wang J, Limsuwan A, Sweeney M, Rubin LJ, Yuan JX. Upregulated TRP and enhanced capacitative Ca2+ entry in human pulmonary artery myocytes during proliferation. Am J Physiol Heart Circ Physiol 280: H746‐H755, 2001.
 100. Gómez‐Angelats M, Bortner CD, Cidlowski JA. Protein kinase C (PKC) inhibits Fas receptor‐induced apoptosis through modulation of the loss of K+ and cell shrinkage. J Biol Chem 275: 19609‐19619, 2000.
 101. Goodenough DA, Paul DL. Beyond the gap: Functions of unpaired connexon channels. Nat Rev Mol Cell Biol 4: 285‐294, 2003.
 102. Guan Z, Pollock JS, Cook AK, Hobbs JL, Inscho EW. Effect of epithelial sodium channel blockade on the myogenic response of rat juxtamedullary afferent arterioles. Hypertension 54: 1062‐1069, 2009.
 103. Guerini D, Coletto L, Carafoli E. Exporting calcium from cells. Cell Calcium 38: 281‐289, 2005.
 104. Gulbis JM, Zhou M, Mann S, MacKinnon R. Structure of the cytoplasmic beta subunit‐T1 assembly of voltage‐dependent K+ channels. Science 289: 123‐127, 2000.
 105. Guo L, Tang X, Tian H, Liu Y, Wang Z, Wu H, Wang J, Guo S, Zhu D. Subacute hypoxia suppresses Kv3.4 channel expression and whole‐cell K+ currents through endogenous 15‐hydroxyeicosatetraenoic acid in pulmonary arterial smooth muscle cells. Eur J Pharmacol 587: 187‐195, 2008.
 106. Gurney AM, Joshi S, Manoury B. KCNQ potassium channels: New targets for pulmonary vasodilator drugs? Adv Exp Med Biol 661: 405‐417, 2010.
 107. Gurney AM, Osipenko ON, MacMillan D, Kempsill FEJ. Potassium channels underlying the resting potential of pulmonary artery smooth muscle cells. Clin Exp Pharmacol Physiol 29: 330‐333, 2002.
 108. Gurney AM, Osipenko ON, MacMillan D, McFarlane KM, Tate RJ, Kempsill FEJ. Two‐pore domain K channel, TASK‐1, in pulmonary artery smooth muscle cells. Circ Res 93: 957‐964, 2003.
 109. Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stuhmer W, Wang X. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage‐gated potassium channels. Pharmacol Rev 57: 473‐508, 2005.
 110. Hart P, Warth JD, Levesque PC, Collier ML, Geary Y, Horowitz B, Hume JR. Cystic fibrosis gene encodes a cAMP‐dependent chloride channel. Proc Natl Acad Sci U S A 93: 6343‐6348, 1996.
 111. Himpens B, De Smedt H, Droogmans G, Casteels R. Differences in regulation between nuclear and cytoplasmic Ca2+ in cultured smooth muscle cells. Am J Physiol 263: C95‐C105, 1992.
 112. Hirenallur SD, Haworth ST, Leming JT, Chang J, Hernandez G, Gordon JB, Rusch NJ. Upregulation of vascular calcium channels in neonatal piglets with hypoxia‐induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 295: L915‐924, 2008.
 113. Hockerman GH, Peterson BZ, Johnson BD, Catterall WA. Molecular determinants of drug binding and action on L‐type calcium channels. Annu Rev Pharmacol Toxicol 37: 361‐396, 1997.
 114. Hofmann T, Schaefer M, Schultz G, Gudermann T. Subunit composition of mammalian transient receptor potential channels in living cells. Proc Natl Acad Sci U S A 99: 7461‐7466, 2002.
 115. Hogg RC, Wang Q, Helliwell RM, Large WA. Properties of spontaneous inward currents in rabbit pulmonary artery smooth muscle cells. Pflügers Arch 425: 233‐240, 1993.
 116. Huang W, Yen RT, McLaurine M, Bledsoe G. Morphometry of the human pulmonary vasculature. J Appl Physiol 81: 2123‐2133, 1996.
 117. Hughes FM, Jr, Bortner CD, Purdy GD, Cidlowski JA. Intracellular K+ suppresses the activation of apoptosis in lymphocytes. J Biol Chem 272: 30567‐30576, 1997.
 118. Hulme JT, Coppock EA, Felipe A, Martens JR, Tamkun MM. Oxygen sensitivity of cloned voltage‐gated K+ channels expressed in the pulmonary vasculature. Circ Res 85: 489‐497, 1999.
 119. Inoue R, Jensen LJ, Shi J, Morita H, Nishida M, Honda A, Ito Y. Transient receptor potential channels in cardiovascular function and disease. Circ Res 99: 119‐131, 2006.
 120. Isakson BE, Duling BR. Heterocellular contact at the myoendothelial junction influences gap junction organization. Circ Res 97: 44‐51, 2005.
 121. Isakson BE, Ramos SI, Duling BR. Ca2+ and inositol 1,4,5‐trisphosphate‐mediated signaling across the myoendothelial junction. Circ Res 100: 246‐254, 2007.
 122. Ishiguro M, Wellman TL, Honda A, Russell SR, Tranmer BI, Wellman GC. Emergence of a R‐Type Ca2+ channel (CaV2.3) contributes to cerebral artery constriction after subarachnoid hemorrhage. Circ Res 96: 419‐426, 2005.
 123. Jang AS, Lee JU, Choi IS, Park KO, Lee JH, Park SW, Park CS. Expression of nitric oxide synthase, aquaporin 1 and aquaporin 5 in rat after bleomycin inhalation. Intensive Care Med 30: 489‐495, 2004.
 124. Jernigan NL, Drummond HA. Vascular ENaC proteins are required for renal myogenic constriction. Am J Physiol Renal Physiol 289: F891‐F901, 2005.
 125. Jernigan NL, Drummond HA. Myogenic vasoconstriction in mouse renal interlobar arteries: Role of endogenous beta and gammaENaC. Am J Physiol Renal Physiol 291: F1184‐F1191, 2006.
 126. Jernigan NL, Walker BR, Resta TC. Chronic hypoxia augments protein kinase G‐mediated Ca2+ desensitization in pulmonary vascular smooth muscle through inhibition of RhoA/Rho kinase signaling. Am J Physiol Lung Cell Mol Physiol 287: L1220‐L1229, 2004.
 127. Jiang ZL, Kassab GS, Fung YC. Diameter‐defined Strahler system and connectivity matrix of the pulmonary arterial tree. J Appl Physiol 76: 882‐892, 1994.
 128. Jo T, Nagata T, Iida H, Imuta H, Iwasawa K, Ma J, Hara K, Omata M, Nagai R, Takizawa H, Nagase T, Nakajima T. Voltage‐gated sodium channel expressed in cultured human smooth muscle cells: Involvement of SCN9A. FEBS Lett 567: 339‐343, 2004.
 129. Joshi S, Balan P, Gurney AM. Pulmonary vasoconstrictor action of KCNQ potassium channel blockers. Respir Res 7: 31‐40, 2006.
 130. Joshi S, Sedivy V, Hodyc D, Herget J, Gurney AM. KCNQ modulators reveal a key role for KCNQ potassium channels in regulating the tone of rat pulmonary artery smooth muscle. J Pharmacol Exp Ther 329: 368‐376, 2009.
 131. Katoh M, Nakajima M, Shimada N, Yamazaki H, Yokoi T. Inhibition of human cytochrome P450 enzymes by 1,4‐dihydropyridine calcium antagonists: Prediction of in vivo drug‐drug interactions. Eur J Clin Pharmacol 55: 843‐852, 2000.
 132. Kinnear NP, Wyatt CN, Clark JH, Calcraft PJ, Fleischer S, Jeyakumar LH, Nixon GF, Evans AM. Lysosomes co‐localize with ryanodine receptor subtype 3 to form a trigger zone for calcium signalling by NAADP in rat pulmonary arterial smooth muscle. Cell Calcium 44: 190‐201, 2008.
 133. Ko EA, Burg ED, Platoshyn O, Msefya J, Firth AL, Yuan JX. Functional characterization of voltage‐gated K+ channels in mouse pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 293: C928‐937, 2007.
 134. Ko YS, Yeh HI, Rothery S, Dupont E, Coppen SR, Severs NJ. Connexin make‐up of endothelial gap junctions in the rat pulmonary artery as revealed by immunoconfocal microscopy and triple‐label immunogold electron microscopy. J Histochem Cytochem 47: 683‐692, 1999.
 135. Kobayashi S, Reien Y, Ogura T, Saito T, Masuda Y, Nakaya H. Inhibitory effect of bepridil on hKv1.5 channel current: Comparison with amiodarone and E‐4031. Eur J Pharmacol 430: 149‐157, 2001.
 136. Koh SD, Monaghan K, Sergeant GP, Ro S, Walker RL, Sanders KM, Horowitz B. TREK‐1 regulation by nitric oxide and cGMP‐dependent protein kinase. An essential role in smooth muscle inhibitory neurotransmission. J Biol Chem 276: 44338‐44346, 2001.
 137. Korovkina VP, England SK. Molecular diversity of vascular potassium channel isoforms. Clin Exp Pharmacol Physiol 29: 317‐323, 2002.
 138. Koster JC, Blanco G, Mercer RW. A cytoplasmic region of the Na,K‐ATPase alpha‐subunit is necessary for specific alpha/alpha association. J Biol Chem 270: 14332‐14339, 1995.
 139. Krick S, Platoshyn O, McDaniel SS, Rubin LJ, Yuan JX. Augmented K+ currents and mitochondrial membrane depolarization in pulmonary artery myocyte apoptosis. Am J Physiol Lung Cell Mol Physiol 281: L887‐L894, 2001.
 140. Krick S, Platoshyn O, Sweeney M, Kim H, Yuan JX. Activation of K+ channels induces apoptosis in vascular smooth muscle cells. Am J Physiol Cell Physiol 280: C970‐979, 2001.
 141. Krick S, Platoshyn O, Sweeney M, McDaniel SS, Zhang S, Rubin LJ, Yuan JX. Nitric oxide induces apoptosis by activating K+ channels in pulmonary vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 282: H184‐H193, 2002.
 142. Krupinski T, Beitel GJ. Unexpected roles of the Na‐K‐ATPase and other ion transporters in cell junctions and tubulogenesis. Physiology (Bethesda) 24: 192‐201, 2009.
 143. Kuga T, Kobayashi S, Hirakawa Y, Kanaide H, Takeshita A. Cell cycle‐dependent expression of L‐ and T‐type Ca2+ currents in rat aortic smooth muscle cells in primary culture. Circ Res 79: 14‐19, 1996.
 144. Kumar B, Dreja K, Shah SS, Cheong A, Xu S‐Z, Sukumar P, Naylor J, Forte A, Cipollaro M, McHugh D, Kingston PA, Heagerty AM, Munsch CM, Bergdahl A, Hultgardh‐Nilsson A, Gomez MF, Porter KE, Hellstrand P, Beech DJ. Upregulated TRPC1 channel in vascular injury in vivo and its role in human neointimal hyperplasia. Circ Res 98: 557‐563, 2006.
 145. Kumar NM, Gilula NB. The gap junction communication channel. Cell 84: 381‐388, 1996.
 146. Kunichika N, Yu Y, Remillard CV, Platoshyn O, Zhang S, Yuan JX. Overexpression of TRPC1 enhances pulmonary vasoconstriction induced by capacitative Ca2+ entry. Am J Physiol Lung Cell Mol Physiol 287: L962‐L969, 2004.
 147. Kurata HT, Soon GS, Eldstrom JR, Lu GW, Steele DF, Fedida D. Amino‐terminal determinants of U‐type inactivation of voltage‐gated K+ channels. J Biol Chem 277: 29045‐29053, 2002.
 148. Lamb FS, Clayton GH, Liu B‐X, Smith RL, Barna TJ, Schutte BC. Expression of CLCN voltage‐gated chloride channel genes in human blood vessels. J Mol Cell Cardiol 31: 657‐666, 1999.
 149. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA III., Loyd JE, Nichols WC, Trembath RC; The International PPH Consortium. Heterozygous germline mutations in BMPR2, encoding a TGF‐β receptor, cause familial primary pulmonary hypertension. Nat Genet 26: 81‐84, 2000.
 150. Leblanc N, Leung PM. Indirect stimulation of Ca2+‐activated Cl− current by Na+/Ca2+ exchange in rabbit portal vein smooth muscle. Am J Physiol 268: H1906‐H1917, 1995.
 151. Lesage F, Lazdunski M. Molecular and functional properties of two‐pore‐domain potassium channels. Am J Physiol Renal Physiol 279: F793‐F801, 2000.
 152. Lewis A, Peers C, Ashford LJ, Kemp PJ. Hypoxia inhibits human recombinant large conductance, Ca2+‐activated K+ (maxi‐K) channels by a mechanism which is membrane delimited and Ca2+ sensitive. J Physiol 540: 771‐780, 2002.
 153. Li H, Guo W, Mellor RL, Nerbonne JM. KChIP2 modulates the cell surface expression of Kv 1.5‐encoded K+ channels. J Mol Cell Cardiol 39: 121‐132, 2005.
 154. Li J, Hassan GS, Williams TM, Minetti C, Pestell RG, Tanowitz HB, Frank PG, Sotgia F, Lisanti MP. Loss of caveolin‐1 causes the hyper‐proliferation of intestinal crypt stem cells, with increased sensitivity to whole body gamma‐radiation. Cell Cycle 4: 1817‐1825, 2005.
 155. Li T, Folkesson HG. RNA interference for alpha‐ENaC inhibits rat lung fluid absorption in vivo. Am J Physiol Lung Cell Mol Physiol 290: L649‐L660, 2006.
 156. Lin MJ, Leung GP, Zhang WM, Yang XR, Yip KP, Tse CM, Sham JS. Chronic hypoxia‐induced upregulation of store‐operated and receptor‐operated Ca2+ channels in pulmonary arterial smooth muscle cells: A novel mechanism of hypoxic pulmonary hypertension. Circ Res 95: 496‐505, 2004.
 157. Lin MJ, Yang XR, Cao YN, Sham JS. Hydrogen peroxide‐induced Ca2+ mobilization in pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 292: L1598‐L1608, 2007.
 158. Link TE, Murakami K, Beem‐Miller M, Tranmer BI, Wellman GC. Oxyhemoglobin‐induced expression of R‐type Ca2+ channels in cerebral arteries. Stroke 39: 2122‐2128, 2008.
 159. Liou J, Kim ML, Do Heo W, Jones JT, Myers JW, Ferrell JE Jr, Meyer T. STIM is a Ca2+ sensor essential for Ca2+‐store‐depletion‐triggered Ca2+ influx. Curr Biol 15: 1235‐1241, 2005.
 160. Lioudyno MI, Kozak JA, Penna A, Safrina O, Zhang SL, Sen D, Roos J, Stauderman KA, Cahalan MD. Orai1 and STIM1 move to the immunological synapse and are up‐regulated during T cell activation. Proc Natl Acad Sci U S A 105: 2011‐2016, 2008.
 161. Liu M, Albert AP, Large WA. Facilitatory effect of Ins(1,4,5)P3 on store‐operated Ca2+‐permeable cation channels in rabbit portal vein myocytes. J Physiol 566: 161‐171, 2005.
 162. Liu X, Bandyopadhyay BC, Singh BB, Groschner K, Ambudkar IS. Molecular analysis of a store‐operated and 2‐acetyl‐sn‐glycerol‐sensitive non‐selective cation channel: Heteromeric assembly of TRPC1‐TPRC3. J Biol Chem 280: 21600‐21606, 2005.
 163. Lu R, Alioua A, Kumar Y, Eghbali M, Stefani E, Toro L. MaxiK channel partners: Physiological impact. J Physiol 570: 65‐72, 2006.
 164. Lu W, Wang J, Peng G, Shimoda LA, Sylvester JT. Knockdown of stromal interaction molecule 1 attenuates store‐operated Ca2+ entry and Ca2+ responses to acute hypoxia in pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 297: L17‐L25, 2009.
 165. Lu W, Wang J, Shimoda LA, Sylvester JT. Differences in STIM1 and TRPC expression in proximal and distal pulmonary arterial smooth muscle are associated with differences in Ca2+ responses to hypoxia. Am J Physiol Lung Cell Mol Physiol 295: L104‐L113, 2008.
 166. Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454: 538‐542, 2008.
 167. Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA III., Newman J, Williams D, Galiè N, Manes A, McNeil K, Yacoub M, Mikhail G, Rogers P, Corris P, Humbert M, Dionnai D, Martensson G, Tranebjaerg L, Loyd JE, Trembath RC, Nichols WC. BMPR2 haploinsufficiency as the inherited mechanism for primary pulmonary hypertension. Am J Hum Gen 68: 92‐102, 2001.
 168. MacKinnon R. New insights into the structure and function of potassium channels. Curr Opin Neurobiol 1: 14‐19, 1991.
 169. Madden JA, Keller PA, Kleinman JG. Changes in smooth muscle cell pH during hypoxic pulmonary vasoconstriction: A possible role for ion transporters. Physiol Res 49: 561‐566, 2000.
 170. Madden JA, Vadula KS, Kurup VP. Effects of hypoxia and other vasoactive agents on pulmonary and cerebral artery smooth muscle cells. Am J Physiol 263: L384‐L393, 1992.
 171. Maeno E, Ishizaki Y, Kanaseki T, Akihiro H, Okada Y. Normotonic cell shrinkage because of disordered volume regulation is an early prerequisite to apoptosis. Proc Natl Acad Sci U S A 97: 9487‐9492, 2000.
 172. Makino A, Platoshyn O, Suarez J, Yuan JX, Dillmann WH. Downregulation of connexin40 is associated with coronary endothelial cell dysfunction in streptozotocin‐induced diabetic mice. Am J Physiol Cell Physiol 295: C221‐230, 2008.
 173. Mandal A, Das S, Chakraborti T, Kar P, Ghosh B, Chakraborti S. Solubilization, purification and reconstitution of Ca2+‐ATPase from bovine pulmonary artery smooth muscle microsomes by different detergents: Preservation of native structure and function of the enzyme by DHPC. Biochim Biophys Acta 1760: 20‐31, 2006.
 174. Mandal M, Das S, Chakraborti T, Mandal A, Chakraborti S. Role of matrix metalloprotease‐2 in oxidant activation of Ca2+ ATPase by hydrogen peroxide in pulmonary vascular smooth muscle plasma membrane. J Biosci 28: 205‐213, 2003.
 175. Mandegar M, Fung Y‐CB, Huang W, Remillard CV, Rubin LJ, Yuan JX. Cellular and molecular mechanisms of pulmonary vascular remodeling: Role in the development of pulmonary hypertension. Microvasc Res 68: 75‐103, 2004.
 176. Marban E, Yamagishi T, Tomaselli GF. Structure and function of voltage‐gated sodium channels. J Physiol 508 (Pt 3): 647‐657, 1998.
 177. Marino M, Beny JL, Peyter AC, Bychkov R, Diaceri G, Tolsa JF. Perinatal hypoxia triggers alterations in K+ channels of adult pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 293: L1171‐1182, 2007.
 178. Martens JR, O'Connell K, Tamkun MM. Targeting of ion channels to membrane microdomains: Localization of KV channels to lipid rafts. Trends Pharmacol Sci 25: 16‐21, 2004.
 179. Martens JR, Sakamoto N, Sullivan SA, Grobaski TD, Tamkun MM. Isoform‐specific localization of voltage‐gated K+ channels to distinct lipid raft populations. Targeting of Kv1.5 to caveolae. J Biol Chem 276: 8409‐8414, 2001.
 180. Massagué J, Blain SW, Lo RS. TGFβ signaling in growth control, cancer, and heritable disorders. Cell 103: 295‐309, 2000.
 181. Massagué J, Chen Y‐G. Controlling TGF‐β signaling. Genes Dev 14: 627‐644, 2000.
 182. Matchkov VV, Larsen P, Bouzinova EV, Rojek A, Boedtkjer DM, Golubinskaya V, Pedersen FS, Aalkjaer C, Nilsson H. Bestrophin‐3 (vitelliform macular dystrophy 2‐like 3 protein) is essential for the cGMP‐dependent calcium‐activated chloride conductance in vascular smooth muscle cells. Circ Res 103: 864‐872, 2008.
 183. McMurtry IF. BAY K 8644 potentiates and A23187 inhibits hypoxic vasoconstriction in rat lungs. Am J Physiol 249: H741‐H746, 1985.
 184. McMurtry IF, Davidson AB, Reeves JT, Grover RF. Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs. Circ Res 38: 99‐104, 1976.
 185. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95: 830‐840, 2004.
 186. Means AR. Calcium calmodulin and cell cycle regulation. FEBS Lett 347: 1‐4, 1994.
 187. Michelakis ED, Thebaud B, Weir EK, Archer SL. Hypoxic pulmonary vasoconstriction: Redox regulation of O2‐sensitive K+ channels by a mitochondrial O2‐sensor in resistance artery smooth muscle cells. J Mol Cell Cardiol 37: 1119‐1136, 2004.
 188. Miriel VA, Mauban JRH, Blaustein MP, Wier WG. Local and cellular Ca2+ transients in smooth muscle of pressurized rat resistance arteries during myogenic and agonist stimulation. J Physiol 518: 815‐824, 1999.
 189. Miyazono K, Kusanagi K, Inoue H. Divergence and convergence of TGF‐β/BMP signaling. J Cell Physiol 187: 265‐276, 2001.
 190. Mori Y, Folco E, Koren G. GH3 cell‐specific expression of Kv1.5 gene. Regulation by a silencer containing a dinucleotide repetitive element. J Biol Chem 270: 27788‐27796, 1995.
 191. Mori Y, Matsubara H, Folco E, Siegel A, Koren G. The transcription of a mammalian voltage‐gated potassium channel is regulated by cAMP in a cell‐specific manner. J Biol Chem 268: 26487‐26493, 1993.
 192. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, Yuan JX, Weir EK. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 54: S20‐S31, 2009.
 193. Murray F, Insel PA, Yuan JX. Role of O2‐sensitive K+ and Ca2+ channels in the regulation of the pulmonary circulation: Potential role of caveolae and implications for high altitude pulmonary edema. Respir Physiol Neurobiol 151: 192‐208, 2006.
 194. Murray F, Patel HH, Thistlethwaite PA, Yuan JX, Insel PA. Pivotal role of both adenylyl cyclase and phosphodiesterase in determining cAMP levels in pulmonary artery smooth muscle cells and primary pulmonary hypertension. Proc Am Thorac Soc 2: A706, 2005.
 195. Murray TR, Chen L, Marshall BE, Macarak EJ. Hypoxic contraction of cultured pulmonary vascular smooth muscle cells. Am J Respir Cell Mol Biol 3: 457‐465, 1990.
 196. Musa‐Aziz R, Chen LM, Pelletier MF, Boron WF. Relative CO2/NH3 selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG. Proc Natl Acad Sci U S A 106: 5406‐5411, 2009.
 197. Nakamura K, Shibata Y. Connexin43 expression in network‐forming cells at the submucosal‐muscular border of guinea pig and dog colon. Cells Tissues Organs 165: 16‐21, 1999.
 198. Nietsch HH, Roe MW, Fiekers JF, Moore AL, Lidofsky SD. Activation of potassium and chloride channels by tumor necrosis factor α: Role in liver death. J Biol Chem 275: 20556‐20561, 2000.
 199. Nilius B, Prenen J, Szücs G, Wei L, Tanzi F, Voets T, Droogmans G. Calcium‐activated chloride channels in bovine pulmonary artery endothelial cells. J Physiol 498: 381‐396, 1997.
 200. Noel J, Pouyssegur J. Hormonal regulation, pharmacology, and membrane sorting of vertebrate Na+/H+ exchanger isoforms. Am J Physiol 268: C283‐C296, 1995.
 201. Noskov SY, Berneche S, Roux B. Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands. Nature 431: 830‐834, 2004.
 202. O'Connell AD, Morton MJ, Sivaprasadarao A, Hunter M. Selectivity and interactions of Ba2+ and Cs+ with wild‐type and mutant TASK1 K+ channels expressed in Xenopus oocytes. J Physiol 562: 687‐696, 2005.
 203. Oka M, Fagan KA, Jones PL, McMurtry IF. Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension. Br J Pharmaco 155: 444‐454, 2008.
 204. Okabe K, Kitamura K, Kuriyama H. Features of 4‐aminopyridine sensitive outward current observed in single smooth muscle cells from the rabbit pulmonary artery. Pflügers Arch 409: 561‐568, 1987.
 205. Okabe K, Kitamura K, Kuriyama H. The existence of a highly tetrodotoxin sensitive Na channel in freshly dispersed smooth muscle cells of the rabbit main pulmonary artery. Pflügers Arch 411: 423‐428, 1988.
 206. Olschewski A, Hong Z, Nelson DP, Weir EK. Graded response of K+ current, membrane potential, and [Ca2+]i to hypoxia in pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 283: L1143‐L1150, 2002.
 207. Olschewski A, Li Y, Tang B, Hanze J, Eul B, Bohle RM, Wilhelm J, Morty RE, Brau ME, Weir EK, Kwapiszewska G, Klepetko W, Seeger W, Olschewski H. Impact of TASK‐1 in human pulmonary artery smooth muscle cells. Circ Res 98: 1072‐1080, 2006.
 208. Osipenko ON, Evans AM, Gurney AM. Regulation of the resting potential of rabbit pulmonary artery myocytes by a low threshold, O2‐sensing potassium current. Br J Pharmacol 120: 1461‐1470, 1997.
 209. Osipenko ON, Tate RJ, Gurney AM. Potential role for Kv3.1b channels as oxygen sensors. Circ Res 86: 534‐540, 2000.
 210. Osol G, Mandala M. Maternal uterine vascular remodeling during pregnancy. Physiology (Bethesda) 24: 58‐71, 2009.
 211. Owsianik G, Talavera K, Voets T, Nilius B. Permeation and selectivity of TRP channels. Annu Rev Physiol 68: 685‐717, 2006.
 212. Pande J, Mallhi KK, Sawh A, Szewczyk MM, Simpson F, Grover AK. Aortic smooth muscle and endothelial plasma membrane Ca2+ pump isoforms are inhibited differently by the extracellular inhibitor caloxin 1b1. Am J Physiol Cell Physiol 290: C1341‐C1349, 2006.
 213. Park SJ YH, Earm YE, Kim SJ, Kim JK, Kim SD. . Role of arachidonic acid‐derived metabolites in the control of pulmonary arterial pressure and hypoxic pulmonary vasoconstriction in rats. Br J Anaesth 106: 31‐37, 2011.
 214. Patel AJ, Honoré E. Molecular physiology of oxygen‐sensitive potassium channels. Eur Respir J 18: 221‐227, 2001.
 215. Patel AJ, Lazdunski M, Honoré E. Kv2.1/Kv9.3, a novel ATP‐dependent delayed‐rectifier K+ channel in oxygen‐sensitive pulmonary artery myocytes. EMBO J 16: 6615‐6625, 1997.
 216. Patel AJ, Maingret F, Magnone V, Fosset M, Lazdunski M, Honore E. TWIK‐2, an inactivating 2P domain K+ channel. J Biol Chem 275: 28722‐28730, 2000.
 217. Pedersen SF, Owsianik G, Nilius B. TRP channels: An overview. Cell Calcium 38: 233‐252, 2005.
 218. Peltz A, Sherwani SI, Kotha SR, Mazerik JN, O'Connor Butler ES, Kuppusamy ML, Hagele T, Magalang UJ, Kuppusamy P, Marsh CB, Parinandi NL. Calcium and calmodulin regulate mercury‐induced phospholipase D activation in vascular endothelial cells. Int J Toxicol 28: 190‐206, 2009.
 219. Penna A, Demuro A, Yeromin AV, Zhang SL, Safrina O, Parker I, Cahalan MD. The CRAC channel consists of a tetramer formed by Stim‐induced dimerization of Orai dimers. Nature 456: 116‐120, 2008.
 220. Perchenet L, Clement‐Chomienne O. External nickel blocks human Kv1.5 channels stably expressed in CHO cells. J Membr Biol 183: 51‐60, 2001.
 221. Perchenet L, Hilfiger L, Mizrahi J, Clément‐Chomienne O. Effects of anorexinogen agents on cloned voltage‐gated K+ channel hKv1.5. J Pharmacol Exp Ther 298: 1108‐1119, 2001.
 222. Plane F, Johnson R, Kerr P, Wiehler W, Thorneloe K, Ishii K, Chen T, Cole W. Heteromultimeric Kv1 channels contribute to myogenic control of arterial diameter. Circ Res 96: 216‐224, 2005.
 223. Platoshyn O, Brevnova EE, Burg ED, Yu Y, Remillard CV, Yuan JX. Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 290: C907‐C916, 2006.
 224. Platoshyn O, Ekhterae D, Zhang S, Yuan JX. Apoptosis regulator with caspase recruitment domain (ARC) protects cardiomyocytes by inhibiting K+ channels. FASEB J 16: A1167, 2002.
 225. Platoshyn O, Remillard CV, Fantozzi I, Mandegar M, Sison TT, Zhang S, Burg E, Yuan JX. Diversity of voltage‐dependent K+ channels in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 287: L226‐L238, 2004.
 226. Platoshyn O, Remillard CV, Fantozzi I, Sison T, Yuan JX. Identification of functional voltage‐gated Na+ channels in cultured human pulmonary artery smooth muscle cells. Pflügers Arch 451: 380‐387, 2005.
 227. Platoshyn O, Yu Y, Golovina VA, McDaniel SS, Krick S, Li L, Wang JY, Rubin LJ, Yuan JX. Chronic hypoxia decreases KV channel expression and function in pulmonary artery myocytes. Am J Physiol Lung Cell Mol Physiol 280: L801‐L812, 2001.
 228. Platoshyn O, Yu Y, Remillard CV, Yuan JX. Heterogeneity of hypoxia‐induced decrease in IK(v) and increase [Ca2+]cyt in pulmonary artery smooth muscle cells. FASEB J 20: A399, 2006.
 229. Platoshyn O, Zhang S, McDaniel SS, Yuan JX. Cytochrome c activates K+ channels before inducing apoptosis. Am J Physiol Cell Physiol 283: C1298‐C1305, 2002.
 230. Post JM, Hume JR, Archer SL, Weir EK. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiol 262: C882‐C890, 1992.
 231. Putney JW. Capacitative calcium entry: From concept to molecules. Immunol Rev 231: 10‐22, 2009.
 232. Quignard J‐F, Félétou M, Edwards G, Duhault J, Weston AH, Vanhoutte PM. Role of endothelial cell hyperpolarization in EDHF‐mediated responses in the guinea‐pig carotid artery. Br J Pharmacol 129: 1103‐1112, 2000.
 233. Ratz PH, Berg KM, Urban NH, Miner AS. Regulation of smooth muscle calcium sensitivity: KCl as a calcium‐sensitizing stimulus. Am J Physiol Cell Physiol 288: C769‐C783, 2005.
 234. Reeve HL, Michelakis E, Nelson DP, Weir EK, Archer SL. Alterations in a redox oxygen sensing mechanism in chronic hypoxia. J Appl Physiol 90: 2249‐2256, 2001.
 235. Remillard CV, Tigno DD, Platoshyn O, Burg ED, Brevnova EE, Conger D, Nicholson A, Rana BK, Channick RN, Rubin LJ, O'Connor DT, Yuan JX. Function of Kv1.5 channels and genetic variations in KCNA5 in patients with idiopathic pulmonary arterial hypertension. Am J Physiol Cell Physiol 292 (5): C1837‐C1853, 2007.
 236. Resnik ER, Keck M, Sukovich DJ, Herron JM, Cornfield DN. Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 292: L953‐L959, 2007.
 237. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium‐channel blockers on survival in primary pulmonary hypertension. N Engl J Med 327: 76‐81, 1992.
 238. Rios EJ, Fallon M, Wang J, Shimoda LA. Chronic hypoxia elevates intracellular pH and activates Na+/H+ exchange in pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 289: L867‐L874, 2005.
 239. Rivera A, Ferreira A, Bertoni D, Romero JR, Brugnara C. Abnormal regulation of Mg2+ transport via Na/Mg exchanger in sickle erythrocytes. Blood 105: 382‐386, 2005.
 240. Robertson BE, Kozlowski RZ, Nye PC. Opposing actions of tolbutamide and glibenclamide on hypoxic pulmonary vasoconstriction. Comp Biochem Physiol C 102: 459‐462, 1992.
 241. Robertson TP, Aaronson PI, Ward JPT. Hypoxic vasoconstriction and intracellular Ca2+ in pulmonary arteries: Evidence for PKC‐independent Ca2+ sensitization. Am J Physiol 268: H301‐H307, 1995.
 242. Robertson TP, Dipp M, Ward JPT, Aaronson PI, Evans AM. Inhibition of sustained hypoxic vasoconstriction by Y‐27632 in isolated intrapulmonary arteries and perfused lung of the rat. Br J Pharmacol 131: 5‐9, 2000.
 243. Rodman DM, Reese K, Harral J, Fouty B, Wu S, West J, Hoedt‐Miller M, Tada Y, Li K‐X, Cool C, Fagan K, Cribbs L. Low‐voltage‐activated (T‐type) calcium channels control proliferation of human pulmonary artery myocytes. Circ Res 96: 864‐872, 2005.
 244. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA. STIM1, an essential and conserved component of store‐operated Ca2+ channel function. J Cell Biol 169: 435‐445, 2005.
 245. Roth M, Rupp M, Hofmann S, Mittal M, Fuchs B, Sommer N, Parajuli N, Quanz K, Schubert D, Dony E, Schermuly RT, Ghofrani HA, Sausbier U, Rutschmann K, Wilhelm S, Seeger W, Ruth P, Grimminger F, Sausbier M, Weissmann N. Heme oxygenase‐2 and large‐conductance Ca2+‐activated K+ channels: Lung vascular effects of hypoxia. Am J Respir Crit Care Med 180: 353‐364, 2009.
 246. Salvaterra CG, Goldman WF. Acute hypoxia increases cytosolic calcium in cultured pulmonary arterial myocytes. Am J Physiol 264: L323‐L328, 1993.
 247. Sardet C, Franchi A, Pouyssegur J. Molecular cloning, primary structure, and expression of the human growth factor‐activatable Na+/H+ antiporter. Cell 56: 271‐280, 1989.
 248. Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, Hutter D, Turini P, Hugli O, Cook S, Nicod P, Scherrer U. Salmeterol for the prevention of high‐altitude pulmonary edema. N Engl J Med 346: 1631‐1636, 2002.
 249. Schuster A, Oishi H, Bény JL, Stergiopulos N, Meister JJ. Simultaneous arterial calcium dynamics and diameter measurements: Application to myoendothelial communication. Am J Physiol Heart Circ Physiol 280: H1088‐H1096, 2001.
 250. Schweigel M, Park HS, Etschmann B, Martens H. Characterization of the Na+‐dependent Mg2+ transport in sheep ruminal epithelial cells. Am J Physiol Gastrointest Liver Physiol 290: G56‐G65, 2006.
 251. Sedova M, Blatter LA. Dynamic regulation of [Ca2+]i by plasma membrane Ca2+‐ATPase and Na+/Ca2+ exchange during capacitative Ca2+ entry in bovine vascular endothelial cells. Cell Calcium 25: 333‐343, 1999.
 252. Segal SS, Damon DN, Duling BR. Propagation of vasomotor responses coordinates arteriolar resistances. Am J Physiol 256: H832‐H837, 1989.
 253. Sewing S, Roeper J, Pongs O. Kvβ1 subunit binding specific for Shaker‐related potassium channel α subunits. Neuron 16: 455‐463, 1996.
 254. Sham JSK, Crenshaw BR Jr, Deng L‐H, Shimoda LA, Sylvester JT. Effects of hypoxia in porcine pulmonary arterial myocytes: Roles of KV channel and endothelin‐1. Am J Physiol Lung Cell Mol Physiol 279: L262‐L272, 2000.
 255. Shimoda LA, Manalo DJ, Sham JSK, Semenza GL, Sylvester JT. Partial HIF‐1α deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia. Am J Physiol Lung Cell Mol Physiol 281: L202‐L208, 2001.
 256. Shimoda LA, Sylvester JT, Booth GM, Shimoda TH, Meeker S, Undem BJ, Sham JSK. Inhibition of voltage‐gated K+ currents by endothelin‐1 in human pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 281: L1115‐L1122, 2001.
 257. Shimoda LA, Sylvester JT, Sham JSK. Inhibition of voltage‐gated K+ current in rat intrapulmonary arterial myocytes by endothelin‐1. Am J Physiol 274: L842‐L853, 1998.
 258. Shimoda LA, Sylvester JT, Sham JSK. Chronic hypoxia alters effects of endothelin and angiotensin on K+ currents in pulmonary arterial myocytes. Am J Physiol 277: L431‐L439, 1999.
 259. Singh BB, Liu X, Tang J, Zhu MX, Ambudkar IS. Calmodulin regulates Ca2+‐dependent feedback inhibition of store‐operated Ca2+ influx by interaction with a site in the C terminus of TRPC1. Mol Cell 9: 739‐750, 2002.
 260. Singh I, Knezevic N, Ahmmed GU, Kini V, Malik AB, Mehta D. Gαq‐TRPC6‐mediated Ca2+ entry induces RhoA activation and resultant endothelial cell shape change in response to thrombin. J Biol Chem 282: 7833‐7843, 2007.
 261. Singhal S, Henderson R, Horsfield K, Harding K, Cumming G. Morphometry of the human pulmonary arterial tree. Circ Res 33: 190‐197, 1973.
 262. Skou JC, Esmann M. The Na,K‐ATPase. J Bioenerg Biomembr 24: 249‐261, 1992.
 263. Smirnov SV, Beck R, Tammaro P, Ishii T, Aaronson PI. Electrophysiologically distinct smooth muscle cell subtypes in rat conduit and resistance pulmonary arteries. J Physiol 538: 867‐878, 2002.
 264. Smirnov SV, Robertson TP, Ward JP, Aaronson PI. Chronic hypoxia is associated with reduced delayed rectifier K+ current in rat pulmonary artery muscle cells. Am J Physiol 266: H365‐H370, 1994.
 265. Sohl G, Willecke K. Gap junctions and the connexin protein family. Cardiovasc Res 62: 228‐232, 2004.
 266. Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature 372: 231‐236, 1994.
 267. Stathopulos PB, Zheng L, Ikura M. Stromal interaction molecule (STIM) 1 and STIM2 calcium sensing regions exhibit distinct unfolding and oligomerization kinetics. J Biol Chem 284: 728‐732, 2009.
 268. Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M. Structural and mechanistic insights into STIM1‐mediated initiation of store‐operated calcium entry. Cell 135: 110‐122, 2008.
 269. Stutts MJ, Canessa CM, Olsen JC, Hamrick M, Cohn JA, Rossier BC, Boucher RC. CFTR as a cAMP‐dependent regulator of sodium channels. Science 269: 847‐850, 1995.
 270. Sun H, Tsunenari T, Yau KW, Nathans J. The vitelliform macular dystrophy protein defines a new family of chloride channels. Proc Natl Acad Sci U S A 99: 4008‐4013, 2002.
 271. Sweeney M, Yu Y, Platoshyn O, Zhang S, McDaniel SS, Yuan JX. Inhibition of endogenous TRP1 decreases capacitative Ca2+ entry and attenuates pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol 283: L144‐L155, 2002.
 272. Sweeney M, Yuan JX. Hypoxic pulmonary vasoconstriction: Role of voltage‐gated potassium channels. Respir Res 1: 40‐48, 2000.
 273. Tamaoki J, Kondo M, Takeuchi S, Takemura H, Nagai A. Vasopressin stimulates ciliary motility of rabbit tracheal epithelium: Role of V1b receptor‐mediated Ca2+ mobilization. Am J Respir Cell Mol Biol 19: 293‐299, 1998.
 274. Tang B, Li Y, Nagaraj C, Morty RE, Gabor S, Stacher E, Voswinckel R, Weissmann N, Leithner K, Olschewski H, Olschewski A. Endothelin‐1 inhibits background two‐pore domain channel TASK‐1 in primary human pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 41: 476‐483, 2009.
 275. Thakali KM, Kharade SV, Sonkusare SK, Rhee SW, Stimers JR, Rusch NJ. Intracellular Ca2+ silences L‐type Ca2+ channels in mesenteric veins: Mechanism of venous smooth muscle resistance to calcium channel blockers. Circ Res 106: 739‐747.
 276. Thompson GJ, Langlais C, Cain K, Conley EC, Cohen GM. Elevated extracellular [K+] inhibits death‐receptor‐ and chemical‐mediated apoptosis prior to caspase activation and cytochrome c release. Biochem J 357: 137‐145, 2001.
 277. Tiruppathi C, Freichel M, Vogel SM, Paria BC, Mehta D, Flockerzi V, Malik AB. Impairment of store‐operated Ca2+ entry in TRPC4−/− mice interferes with increase in lung microvascular permeability. Circ Res 91: 70‐76, 2002.
 278. Touyz RM, Schiffrin EL. Activation of the Na+‐H+ exchanger modulates angiotensin II—stimulated Na+‐dependent Mg2+ transport in vascular smooth muscle cells in genetic hypertension. Hypertension 34: 442‐449, 1999.
 279. Townsley M, King J, Alvarez D. Ca2+ channels and pulmonary endothelial permeability: Insights from study of intact lung and chronic pulmonary hypertension. Microcirculation 13: 725‐739, 2006.
 280. Tsien RW, Tsien RY. Calcium channels, stores, and oscillations. Annu Rev Cell Biol 6: 715‐760, 1990.
 281. Tucker A, McMurtry IF, Grover RF, Reeves JT. Attenuation of hypoxic pulmonary vasconstriction by verapamil in intact dog. Proc Soc Exp Biol Med 151: 611‐614, 1976.
 282. Wallner M, Meera P, Toro L. Molecular basis of fast inactivation in voltage and Ca2+‐activated K+ channels: A transmembrane β‐subunit homolog. Proc Natl Acad Sci U S A 96: 4137‐4142, 1999.
 283. Wang H‐S, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE, McKinnon D. KCNQ2 and KCNQ3 potassium channel subunits: Molecular correlates of the M‐channel. Science 282: 1890‐1893, 1998.
 284. Wang J, Juhaszova M, Rubin LJ, Yuan XJ. Hypoxia inhibits gene expression of voltage‐gated K+ channel α subunits in pulmonary artery smooth muscle cells. J Clin Invest 100: 2347‐2353, 1997.
 285. Wang J, Weigand L, Lu W, Sylvester JT, Semenza GL, Shimoda LA. Hypoxia inducible factor 1 mediates hypoxia‐induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells. Circ Res 98: 1528‐1537, 2006.
 286. Wang J, Weigand L, Wang W, Sylvester JT, Shimoda LA. Chronic hypoxia inhibits KV channel gene expression in rat distal pulmonary artery. Am J Physiol Lung Cell Mol Physiol 288: L1049‐L1058, 2005.
 287. Wang LH, Luo M, Wang Y, Galligan JJ, Wang DH. Impaired vasodilation in response to perivascular nerve stimulation in mesenteric arteries of TRPV1‐null mutant mice. J Hypertens 24: 2399‐2407, 2006.
 288. Wang Q, Large WA. Action of histamine on single smooth muscle cells dispersed from the rabbit pulmonary artery. J Physiol 468: 125‐139, 1993.
 289. Wang XL, Ye D, Peterson TE, Cao S, Shah VH, Katusic ZS, Sieck GC, Lee HC. Caveolae targeting and regulation of large conductance Ca2+‐activated K+ channels in vascular endothelial cells. J Biol Chem 280: 11656‐11664, 2005.
 290. Wang Y, Deng X, Hewavitharana T, Soboloff J, Gill DL. Stim, ORAI and TRPC channels in the control of calcium entry signals in smooth muscle. Clin Exp Pharmacol Physiol 35: 1127‐1133, 2008.
 291. Wang YX, Wang J, Wang C, Liu J, Shi LP, Xu M. Functional expression of transient receptor potential vanilloid‐related channels in chronically hypoxic human pulmonary arterial smooth muscle cells. J Membr Biol 223: 151‐159, 2008.
 292. Waypa GB, Chandel NS, Schumacker PT. Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing. Circ Res 88: 1259‐1266, 2001.
 293. Waypa GB, Guzy R, Mungai PT, Mack MM, Marks JD, Roe MW, Schumacker PT. Increases in mitochondrial reactive oxygen species trigger hypoxia‐induced calcium responses in pulmonary artery smooth muscle cells. Circ Res 99: 970‐978, 2006.
 294. Wei Z, Manevich Y, Al‐Mehdi AB, Chatterjee S, Fisher AB. Ca2+ flux through voltage‐gated channels with flow cessation in pulmonary microvascular endothelial cells. Microcirculation 11: 517‐526, 2004.
 295. Weibel ER. Morphometry of the Human Lung. Berlin, Germany: Springer‐Verlag, 1963.
 296. Weir EK, López‐Barneo J, Buckler KJ, Archer SL. Acute oxygen‐sensing mechanisms. N Engl J Med 353: 2042‐2055, 2005.
 297. Whitman EM, Pisarcik S, Luke T, Fallon M, Wang J, Sylvester JT, Semenza GL, Shimoda LA. Endothelin‐1 mediates hypoxia‐induced inhibition of voltage‐gated K+ channel expression in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 294: L309‐318, 2008.
 298. Williams CP, Hu N, Shen W, Mashburn AB, Murray KT. Modulation of the human Kv1.5 channel by protein kinase C activation: Role of the Kvβ1.2 subunit. J Pharmacol Exp Ther 302: 545‐550, 2002.
 299. Wu S, Jian MY, Xu YC, Zhou C, Al‐Mehdi AB, Liedtke W, Shin HS, Townsley MI. Ca2+ entry via α1G and TRPV4 channels differentially regulates surface expression of P‐selectin and barrier integrity in pulmonary capillary endothelium. Am J Physiol Lung Cell Mol Physiol 297: L650‐657, 2009.
 300. Xu S‐Z, Beech DJ. TRPC1 is a membrane‐spanning subunit of store‐operated Ca2+ channels in native vascular smooth muscle cells. Circ Res 88: 84‐87, 2001.
 301. Yamazaki J, Duan D, Janiak R, Kuenzli K, Horowitz B, Hume JR. Functional and molecular expression of volume‐regulated chloride channels in canine vascular smooth muscle cells. J Physiol 507: 729‐736, 1998.
 302. Yang X‐R, Lin M‐J, McIntosh LS, Sham JSK. Functional TRPM and TRPV channel subtypes are expressed in rat intralobar pulmonary arteries and aorta. FASEB J 20: A400, 2006.
 303. Yang X‐R, Lin M‐J, Yip K‐P, Jeyakumar LH, Fleischer S, Leung GPH, Sham JSK. Multiple ryanodine receptor subtypes and heterogeneous ryanodine receptor‐gated Ca2+ stores in pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 289: L338‐L348, 2005.
 304. Yao W, Qian G, Yang X. Roles of NHE‐1 in the proliferation and apoptosis of pulmonary artery smooth muscle cells in rats. Chin Med J (Engl) 115: 107‐109, 2002.
 305. Yen RT, Zhuang FY, Fung YC, Ho HH, Tremer H, Sobin SS. Morphometry of cat pulmonary venous tree. J Appl Physiol 55: 236‐242, 1983.
 306. Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443: 226‐229, 2006.
 307. Ying X, Minamiya Y, Fu C, Bhattacharya J. Ca2+ waves in lung capillary endothelium. Circ Res 79: 898‐908, 1996.
 308. Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, Beaty T, Sham JSK, Wiener CM, Sylvester JT, Semenza GL. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia‐inducible factor 1α. J Clin Invest 103: 691‐696, 1999.
 309. Yu L, Quinn DA, Garg HG, Hales CA. Deficiency of the NHE1 gene prevents hypoxia‐induced pulmonary hypertension and vascular remodeling. Am J Respir Crit Care Med 177: 1276‐1284, 2008.
 310. Yu SP, Yeh C‐H, Sensi SL, Gwag BJ, Canzoniero LMT, Farhangrazi ZS, Ying HS, Tian M, Dugan LL, Choi DW. Mediation of neuronal apoptosis by enhancement of outward potassium current. Science 278: 114‐117, 1997.
 311. Yu Y, Fantozzi I, Remillard CV, Landsberg JW, Kunichika N, Platoshyn O, Tigno DD, Thistlethwaite PA, Rubin LJ, Yuan JX. Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc Natl Acad Sci USA 101: 13861‐13866, 2004.
 312. Yu Y, Keller SH, Remillard CV, Safrina O, Nicholson A, Zhang SL, Jiang W, Vangala N, Landsberg JW, Wang JY, Thistlethwaite PA, Channick RN, Robbins IM, Loyd JE, Ghofrani HA, Grimminger F, Schermuly RT, Cahalan MD, Rubin LJ, Yuan JX. A functional single‐nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation 119: 2313‐2322, 2009.
 313. Yu Y, Platoshyn O, Zhang J, Krick S, Zhao Y, Rubin LJ, Rothman A, Yuan JX. c‐Jun decreases voltage‐gated K+ channel activity in pulmonary artery smooth muscle cells. Circulation 104: 1557‐1563, 2001.
 314. Yu Y, Sweeney M, Zhang S, Platoshyn O, Landsberg J, Rothman A, Yuan JX. PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am J Physiol Cell Physiol 284: C316‐330, 2003.
 315. Yuan JX. Hypoxic Pulmonary Vasoconstriction: Cellular and Molecular Mechanisms. Boston, MA: Kluwer Academic Publishers, 2004.
 316. Yuan JX. Ion Channels in the Pulmonary Vasculature. New York, NY: Taylor & Francis, 2005.
 317. Yuan JX, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP, Orens JB, Rubin LJ. Dysfunctional voltage‐gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 98: 1400‐1406, 1998.
 318. Yuan XJ. Voltage‐gated K+ currents regulate resting membrane potential and [Ca2+]i in pulmonary arterial myocytes. Circ Res 77: 370‐378, 1995.
 319. Yuan XJ. Role of calcium‐activated chloride current in regulating pulmonary vascular tone. Am J Physiol 272: L959‐L968, 1997.
 320. Yuan XJ, Goldman WF, Tod ML, Rubin LJ, Blaustein MP. Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes. Am J Physiol 264: L116‐L123, 1993.
 321. Yuan XJ, Tod ML, Rubin LJ, Blaustein MP. Contrasting effects of hypoxia on tension in rat pulmonary and mesenteric arteries. Am J Physiol 259: H281‐H289, 1990.
 322. Yuan XJ, Tod ML, Rubin LJ, Blaustein MP. Deoxyglucose and reduced glutathione mimic effects of hypoxia on K+ and Ca2+ conductances in pulmonary artery cells. Am J Physiol 267: L52‐L63, 1994.
 323. Yuan XJ, Wang J, Juhaszova M, Gaine SP, Rubin LJ. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet 351: 726‐727, 1998.
 324. Zhang S, Dong H, Rubin LJ, Yuan JX. Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Am J Physiol Cell Physiol 292: C2297‐2305, 2007.
 325. Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA, Kriett JM, Yung G, Rubin LJ, Yuan JX. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285: L740‐L754, 2003.
 326. Zhang S, Patel HH, Murray F, Remillard CV, Schach C, Thistlethwaite P, Insel PA, Yuan JX. Pulmonary artery smooth muscle cells from normal subjects and IPAH patients show divergent cAMP‐mediated effects on TRPC expression and capacitative Ca2+ entry. Am J Physiol Lung Cell Mol Physiol 292: L1202‐L1210, 2007.
 327. Zhang S, Remillard CV, Fantozzi I, Yuan JX. ATP‐induced mitogenesis is mediated by cyclic AMP response element‐binding protein‐enhanced TRPC4 expression and activity in human pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 287: C1192‐1201, 2004.
 328. Zhang S, Yuan JX, Barrett KE, Dong H. Role of Na+/Ca2+ exchange in regulating cytosolic Ca2+ in cultured human pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 288: C245‐252, 2005.
 329. Zhang W‐M, Lin M‐J, Sham JSK. Endothelin‐1 and IP3 induced Ca2+ sparks in pulmonary arterial smooth muscle cells. J Cardiovasc Pharmacol 44: S121‐S124, 2004.
 330. Zheng YM, Wang YX. Sodium‐calcium exchanger in pulmonary artery smooth muscle cells. Ann N Y Acad Sci 1099: 427‐435, 2007.
 331. Zhu MX, Ma J, Parrington J, Calcraft PJ, Galione A, Evans AM. Calcium signaling via two‐pore channels: Local or global, that is the question. Am J Physiol Cell Physiol 298: C430‐441.
Further Reading
 1. Yuan JX‐J, (ed). Hypoxic Pulmonary Vasoconstriction: Cellular and Molecular Mechanisms. Boston, MA: Kluwer Academic Publishers, 2004.
 2. Yuan JX‐J, (ed). Ion Channels in the Pulmonary Vasculature. Boca Raton, FL: Taylor & Francis Group, 2005.
 3. Yuan JX‐J, Ward JPT, (eds). Membrane Receptors, Channels, and Transporters in Pulmonary Circulation. New York, NY: Humana Press‐Springer, 2010.
 4. Yuan JX‐J, Garcia JGG, Hales CA, Rich S, Archer SL, West JB, (eds). Textbook of Pulmonary Vascular Disease. Springer, New York, NY, 2011.

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Ayako Makino, Amy L. Firth, Jason X.‐J. Yuan. Endothelial and Smooth Muscle Cell Ion Channels in Pulmonary Vasoconstriction and Vascular Remodeling. Compr Physiol 2011, 1: 1555-1602. doi: 10.1002/cphy.c100023