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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 229.

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. 82.
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 210. (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 229.



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. 82.


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 210. (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.

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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