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Cytoskeletal Dynamics and Lung Fluid Balance

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Abstract

This article examines the role of the endothelial cytoskeleton in the lung's ability to restrict fluid and protein to vascular space at normal vascular pressures and thereby to protect lung alveoli from lethal flooding. The barrier properties of microvascular endothelium are dependent on endothelial cell contact with other vessel‐wall lining cells and with the underlying extracellular matrix (ECM). Focal adhesion complexes are essential for attachment of endothelium to ECM. In quiescent endothelial cells, the thick cortical actin rim helps determine cell shape and stabilize endothelial adherens junctions and focal adhesions through protein bridges to actin cytoskeleton. Permeability‐increasing agonists signal activation of “small GTPases” of the Rho family to reorganize the actin cytoskeleton, leading to endothelial cell shape change, disassembly of cortical actin rim, and redistribution of actin into cytoplasmic stress fibers. In association with calcium‐ and Src‐regulated myosin light chain kinase (MLCK), stress fibers become actinomyosin‐mediated contractile units. Permeability‐increasing agonists stimulate calcium entry and induce tyrosine phosphorylation of VE‐cadherin (vascular endothelial cadherin) and β‐catenins to weaken or pull apart endothelial adherens junctions. Some permeability agonists cause latent activation of the small GTPases, Cdc42 and Rac1, which facilitate endothelial barrier recovery and eliminate interendothelial gaps. Under the influence of Cdc42 and Rac1, filopodia and lamellipodia are generated by rearrangements of actin cytoskeleton. These motile evaginations extend endothelial cell borders across interendothelial gaps, and may initiate reannealing of endothelial junctions. Endogenous barrier protective substances, such as sphingosine‐1‐phosphate, play an important role in maintaining a restrictive endothelial barrier and counteracting the effects of permeability‐increasing agonists. © 2012 American Physiological Society. Compr Physiol 2:449‐478, 2012.

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Figure 1. Figure 1.

Transition between quiescent and active endothelial phenotypes. Left: Endothelial cell activation by permeability‐increasing agonist. Binding of thrombin to its receptor increases intracellular Ca2+, which forms a complex with calmodulin (CaM) that can activate myosin light chain kinase (MLCK). Phosphorylated form of myosin light chain (MLC) stimulates actinomyosin‐based endothelial contractility, which leads to the formation of interendothelial gaps. Examples of regulatory molecules that increase or decrease endothelial contractility are depicted in green or white, respectively: Src kinases (pp60src) increase MLCK activity by tyrosine phosphorylation; rho kinase augments EC contractility by inhibiting both MLC phosphatase and the actin‐depolymerizing protein, cofilin; p38 mitogen‐activated protein kinase (MAPK) inhibits heat shock protein (HSP) 27 activity to promote actin stress fiber formation, as does the actin‐associated capping/severing protein gelsolin. Right: Quiescent endothelial cells possess a thick cortical actin rim, and adhere tightly to each other via interendothelial junctional complexes (tight junctions and adherens junctions) and to the underlying ECM via focal adhesions. Tight junctions consist of transmembrane occludin proteins linked to the endothelial actin cytoskeleton by proteins of the zona occludins family (ZO‐1). Adherens junctions mediate cell‐cell contact through homotypic binding between the extracellular domains of endothelial‐specific VE‐cadherin, and are stabilized by protein bridges between the cytoplasmic tail of VE‐cadherin and cortical actin rim that include, among other components, β/γ‐catenins (plakoglobin) and α‐catenin. The tyrosine phosphatase SHP2 may contribute to stability of adherens junctions by decreasing tyrosine phosphorylation of catenins. Platelet endothelial cell adhesion molecule‐1 (PECAM‐1) is concentrated in intercellular clefts, but it is not associated specifically with adherens or tight junctions; PECAM‐1 can mediate homotypic or heterotypic binding to an adjacent cell, and is internally tethered to cortical actin rim . Focal adhesion plaques consisting of talin, paxillin (Pax), vinculin (Vin), α‐actinin (A), and focal adhesion kinase (FAK) link endothelial integrins to cortical actin rim to stabilize focal adhesions. Sphingosine‐1‐phosphate (S‐1‐P) binding to its receptor promotes quiescent endothelial phenotype and counteracts the effects of permeability‐increasing agonists such as thrombin. PAR‐1, protein‐activated receptor‐1; EDG receptor, endothelial differentiation gene receptor. American Physiological Society, used with permission .

Figure 2. Figure 2.

Separate fluid and protein transport pathways through microvessel endothelium. Fluid moves through paracellular pathway according to Starling forces. Protein is transported through endothelial cells via vesicles or transendothelial channels. Because the protein and fluid pathways are separated, local protein gradients can theoretically develop in the interstitium. American Physiological Society, used with permission .

Figure 3. Figure 3.

The vesicular protein‐transport pathway in pulmonary microvascular endothelium. Main electron micrograph shows labeling of endothelial vesicles with the vascular tracer dinitrophenol‐conjugated albumin (A‐DNP) in a murine postcapillary venule. Inset image is similar except that it depicts albumin transport in a murine lung capillary. Albumin detection was with an electron opaque anti‐DNP antibody. Note abundant labeling of endothelial caveolae in both microvessels at various stages of albumin transcytosis and absence of the tracer molecule (diameter 12 nm) from interendothelial space (see inset). Calibration bars are 100 nm (main image) and 80 nm (inset). PVS, perivascular space. American Physiological Society, used with permission .

Figure 4. Figure 4.

Starling forces acting on lung microvessel walls. P, π, and σ denote hydrostatic pressure, oncotic pressure, and osmotic reflection coefficient, respectively. ΔP is the net pulmonary driving pressure, which is normally outward. In mild hydrostatic edema, capillary pressure is elevated, leading to an intertstitial edema. In hypoproteinemia, oncotic pressure difference is reduced causing an interstitial edema. Int, interstitium; cap, capillary.

Figure 5. Figure 5.

Formation of protein‐rich pulmonary edema fluid. Normal and injured alveolar‐capillary barriers are illustrated in left and right panels. In the acute phase of ARDS (acute respiratory distress syndrome), capillary endothelium is damaged and neutrophils adherent to injured capillary endothelium migrate through vessel wall and into alveolar space. Endothelial swelling and blebbing takes place and prominent interendothelial gaps form, thereby compromising the endothelial barrier to blood cells and plasma. Platelets aggregate on damaged vessel wall. Pulmonary interstitium is dilated due to fluid accumulation. Alveolar macrophages release interleukins (IL‐1, 6, 8, and 10) and TNFα, further stimulating neutrophil margination and migration. IL‐1 can also stimulate interstitial fibroblasts to generate ECM proteins. Neutrophils release oxidants, proteases, leukotrienes, and platelet‐activating factor. Damaged epithelial cells become detached from basement membrane and are replaced with proteinaceous hyaline “membranes.” As the alveolar‐capillary barrier deteriorates, increasing numbers of alveoli become flooded with fluid rich in plasma proteins, which inactivates surfactant. Hence, loss of alveolar‐epithelial barrier function leads to protein‐rich edema. MIF, macrophage inhibitory factor. Reprinted with permission of the American Thoracic Society. Copyright© American Thoracic Society .

Figure 6. Figure 6.

Actin microfilaments. (A) Electron micrograph of an actin microfilament decorated with myosin heads. (B) Model of elongation of microfilament. Ratio of dissociation rate constant (s−1) to association rate constant (μM−1 s−1) gives K, the equilibrium dissociation constant (μM). ATP‐bound actin monomer has a higher affinity for barbed end than for pointed end. Reprinted, with permission, from reference .

Figure 7. Figure 7.

Organization of microtubule cytoskeleton in monolayer of human lung microvascular endothelial cells (HLMVECs). (A) Microtubules (yellow) extend from the microtubule‐organizing center (MTOC) to cell periphery; nuclei are stained in blue (Image courtesy of Dr. Yulia Komarova). (B) Schematic diagram of the microtubule (MT) cytoskeleton. Minus ends of MTs attach to centrosome (yellow) and plus ends grow radially toward cell periphery. MTs serve as tracks for mobile vesicles, which move from centrosome to cell periphery (red circles) or backwards toward the centrosome (green circles). Reprinted, with permission, from reference .

Figure 8. Figure 8.

Growth and shrinkage of microtubules (MT). Presence of GTP–(α, β)‐tubulin (pink) at the plus end stabilizes the growth phase of MT. GTP hydrolysis results in rapid MT shrinkage, with individual protofilaments bending away from the microtubule axis. The transition from growth to shrinkage is referred to as catastrophe; transition from shrinkage to growth is known as rescue. Reprinted, with permission, from reference .

Figure 9. Figure 9.

Activation of LIM kinase 1 (LIMK1) destabilizes pulmonary interendothelial junctions. (A and B) Electron micrographs of interendothelial junctions (arrows) in WT (A) and limk1–/– mice (B) without and with PAR‐1 peptide agonist as indicated. Magnification, 60,000. (C) Morphometric analysis of open interendothelial junctions induced by exposure of mouse lungs to PAR‐1 agonist. Each bar shows percentage of open junctions out of 50 observations made. PAR‐1 agonist induced significantly more open junctions in WT lungs (P = 0.010197). Error bars represent SEM. Reprinted, with permission, from reference .

Figure 10. Figure 10.

Interendothelial junctions in quiescent cells. (A) Diagram of endothelial adherens junctions and their relationship to actin cytoskeleton. Homotypic adhesion between extracellular domains (EXDS) of VE‐cadherin molecules joins adjacent cells. The juxtramembrane domain (JMD) of VE‐cadherin binds p120 (aqua), a protein regulating the stability of adherens junctions. The carboxyl‐terminal domain (CTD) binds exclusively to either β‐catenin or γ‐catenin (plakoglobin; green), which in turn binds to α‐catenin (dark blue). α‐Catenin interacts with F‐actin directly and indirectly through binding to α‐actinin (light orange) to create a strong link between VE‐cadherin and actin cytoskeleton. Vinculin, another actin‐associated protein, is also depicted (violet). (B) Diagram illustrating endothelial tight junctions. Homotypic adhesion between EXDs of occludin molecules (green) creates the tight junctional contact. The cytoplasmic carboxyl domain of occludin binds to ZO‐1 (red), which is indirectly linked to actin cytoskeleton via α‐catenin (dark blue). Reprinted, with permission, from reference .

Figure 11. Figure 11.

Organization of actin and microtubule cytoskeletons and their relationship to adherens junctions. Monolayer of quiescent human lung microvascular endothelial cells was stained for VE‐cadherin (red), α‐tubulin and actin (green, as indicated), and DNA (blue). Actin organizes into peripheral actin bundles along the VE‐cadherin‐mediated adhesions. Microtubules extend from the centrosome throughout the cell. Image courtesy of Dr.Yulia Komarova.

Figure 12. Figure 12.

Organization of focal adhesions. (A) Immunostaining of endothelial monolayer for actin (green) and focal‐adhesion protein, vinculin (red). (B) Diagram of the focal adhesion complex, showing integrin bound to ECM protein and its intracellular linkage to F‐actin. Image courtesy of Dr. Richard Minshall.

Figure 13. Figure 13.

Receptor control of microvessel permeability. Permeability‐increasing agonist such as thrombin, ligates proteinase‐activated receptor‐1 (PAR‐1), stimulating Gαq and Gα12/13. Gαq triggers increased intracellular Ca2+, which activates EC MLCK (endothelial‐cell myosin light chain kinase) and hence elevates the phosphorylation level of MLC (MLC‐P). Increased intracellular Ca2+ also activates protein kinases, such as PKCα (not shown), which phosphorylate GDI‐1 (GDP‐dissociation inhibitor) and p115RhoGEF (guanine nucleotide exchange factor), thereby increasing the activity of RhoA GTPase. RhoA activates ROCK (rho kinase) and LIMK1 (LIM kinase‐1), which regulates actin binding proteins (cofilin) and thus the state of actin polymerization. ROCK by phosphorylating MLC phosphatase (Ppase) inhibits Ppase and thus increases MLC‐P. Together, these events lead to increased actin‐myosin cross‐bridging, resulting in increased endothelial contraction. Image courtesy of Dr. Dolly Mehta.

Figure 14. Figure 14.

Mechanism of lamellipodia and filopodia formation. (A) Organization of actin cytoskeleton in lamellipodia of fish epidermal keratocytes. Reproduced, with permission, from reference . (B and C) Organization of actin cytoskeleton in filopodia embedded in lamellipodium in B16F1 melanoma cell. (B) Fluorescent image. Region enclosed by rectangle is enlarged in insets. Reproduced, with permission, from reference . (C) Platinum replica EM. Filopodium contains a tight bundle of actin filaments. Inset shows branched actin on surface of lamellipodium. Reproduced, with permission, from reference . (D and E) Model for mechanism of lamellipodial (top) and filopodial (bottom) protrusion depending on capping activity in cells. Top: When capping activity dominates either by activation of CP (capping protein) or inhibition of capping antagonists such as Ena/VASP‐like protein (enabled/ vasodilator‐stimulated phosphoprotein), filaments elongate for a brief period before becoming capped and, as a consequence, these filaments are relatively short. To maintain protrusion, capped filaments are replaced by newly nucleated side branches produced by Arp2/3 complex, favoring the formation of a branching, lamellipodial network. Bottom: Low‐capping activity resulting either from inhibition of CP or activation of proteins that promote anticapping and antibranching such as Ena/VASP, favor filament elongation leading to long and unbranched filaments, which converge and subsequently become bundled by actin cross‐linking molecule, fascin. Filopodia formation is therefore predominant. Modified, with permission, from reference .

Figure 15. Figure 15.

Thrombin‐induced stress fiber formation in endothelial cells (murine lung). Actin is stained in green and nuclei, in blue. Image courtesy of Dr. C. Tiruppathi.

Figure 16. Figure 16.

Intracellular distribution of VE‐cadherin in resting endothelial cells and in cells challenged with pro‐inflammatory mediator, thrombin. Confluent monolayers of HLMVECs, either untreated or treated with 50 nM human α‐thrombin for 30 min, were stained for VE‐cadherin (yellow) and DNA (blue). Thrombin induces disruption of VE‐cadherin‐mediated adhesions and formation of gaps between cells. (Images courtesy of Emily Vandenbroucke).



Figure 1.

Transition between quiescent and active endothelial phenotypes. Left: Endothelial cell activation by permeability‐increasing agonist. Binding of thrombin to its receptor increases intracellular Ca2+, which forms a complex with calmodulin (CaM) that can activate myosin light chain kinase (MLCK). Phosphorylated form of myosin light chain (MLC) stimulates actinomyosin‐based endothelial contractility, which leads to the formation of interendothelial gaps. Examples of regulatory molecules that increase or decrease endothelial contractility are depicted in green or white, respectively: Src kinases (pp60src) increase MLCK activity by tyrosine phosphorylation; rho kinase augments EC contractility by inhibiting both MLC phosphatase and the actin‐depolymerizing protein, cofilin; p38 mitogen‐activated protein kinase (MAPK) inhibits heat shock protein (HSP) 27 activity to promote actin stress fiber formation, as does the actin‐associated capping/severing protein gelsolin. Right: Quiescent endothelial cells possess a thick cortical actin rim, and adhere tightly to each other via interendothelial junctional complexes (tight junctions and adherens junctions) and to the underlying ECM via focal adhesions. Tight junctions consist of transmembrane occludin proteins linked to the endothelial actin cytoskeleton by proteins of the zona occludins family (ZO‐1). Adherens junctions mediate cell‐cell contact through homotypic binding between the extracellular domains of endothelial‐specific VE‐cadherin, and are stabilized by protein bridges between the cytoplasmic tail of VE‐cadherin and cortical actin rim that include, among other components, β/γ‐catenins (plakoglobin) and α‐catenin. The tyrosine phosphatase SHP2 may contribute to stability of adherens junctions by decreasing tyrosine phosphorylation of catenins. Platelet endothelial cell adhesion molecule‐1 (PECAM‐1) is concentrated in intercellular clefts, but it is not associated specifically with adherens or tight junctions; PECAM‐1 can mediate homotypic or heterotypic binding to an adjacent cell, and is internally tethered to cortical actin rim . Focal adhesion plaques consisting of talin, paxillin (Pax), vinculin (Vin), α‐actinin (A), and focal adhesion kinase (FAK) link endothelial integrins to cortical actin rim to stabilize focal adhesions. Sphingosine‐1‐phosphate (S‐1‐P) binding to its receptor promotes quiescent endothelial phenotype and counteracts the effects of permeability‐increasing agonists such as thrombin. PAR‐1, protein‐activated receptor‐1; EDG receptor, endothelial differentiation gene receptor. American Physiological Society, used with permission .



Figure 2.

Separate fluid and protein transport pathways through microvessel endothelium. Fluid moves through paracellular pathway according to Starling forces. Protein is transported through endothelial cells via vesicles or transendothelial channels. Because the protein and fluid pathways are separated, local protein gradients can theoretically develop in the interstitium. American Physiological Society, used with permission .



Figure 3.

The vesicular protein‐transport pathway in pulmonary microvascular endothelium. Main electron micrograph shows labeling of endothelial vesicles with the vascular tracer dinitrophenol‐conjugated albumin (A‐DNP) in a murine postcapillary venule. Inset image is similar except that it depicts albumin transport in a murine lung capillary. Albumin detection was with an electron opaque anti‐DNP antibody. Note abundant labeling of endothelial caveolae in both microvessels at various stages of albumin transcytosis and absence of the tracer molecule (diameter 12 nm) from interendothelial space (see inset). Calibration bars are 100 nm (main image) and 80 nm (inset). PVS, perivascular space. American Physiological Society, used with permission .



Figure 4.

Starling forces acting on lung microvessel walls. P, π, and σ denote hydrostatic pressure, oncotic pressure, and osmotic reflection coefficient, respectively. ΔP is the net pulmonary driving pressure, which is normally outward. In mild hydrostatic edema, capillary pressure is elevated, leading to an intertstitial edema. In hypoproteinemia, oncotic pressure difference is reduced causing an interstitial edema. Int, interstitium; cap, capillary.



Figure 5.

Formation of protein‐rich pulmonary edema fluid. Normal and injured alveolar‐capillary barriers are illustrated in left and right panels. In the acute phase of ARDS (acute respiratory distress syndrome), capillary endothelium is damaged and neutrophils adherent to injured capillary endothelium migrate through vessel wall and into alveolar space. Endothelial swelling and blebbing takes place and prominent interendothelial gaps form, thereby compromising the endothelial barrier to blood cells and plasma. Platelets aggregate on damaged vessel wall. Pulmonary interstitium is dilated due to fluid accumulation. Alveolar macrophages release interleukins (IL‐1, 6, 8, and 10) and TNFα, further stimulating neutrophil margination and migration. IL‐1 can also stimulate interstitial fibroblasts to generate ECM proteins. Neutrophils release oxidants, proteases, leukotrienes, and platelet‐activating factor. Damaged epithelial cells become detached from basement membrane and are replaced with proteinaceous hyaline “membranes.” As the alveolar‐capillary barrier deteriorates, increasing numbers of alveoli become flooded with fluid rich in plasma proteins, which inactivates surfactant. Hence, loss of alveolar‐epithelial barrier function leads to protein‐rich edema. MIF, macrophage inhibitory factor. Reprinted with permission of the American Thoracic Society. Copyright© American Thoracic Society .



Figure 6.

Actin microfilaments. (A) Electron micrograph of an actin microfilament decorated with myosin heads. (B) Model of elongation of microfilament. Ratio of dissociation rate constant (s−1) to association rate constant (μM−1 s−1) gives K, the equilibrium dissociation constant (μM). ATP‐bound actin monomer has a higher affinity for barbed end than for pointed end. Reprinted, with permission, from reference .



Figure 7.

Organization of microtubule cytoskeleton in monolayer of human lung microvascular endothelial cells (HLMVECs). (A) Microtubules (yellow) extend from the microtubule‐organizing center (MTOC) to cell periphery; nuclei are stained in blue (Image courtesy of Dr. Yulia Komarova). (B) Schematic diagram of the microtubule (MT) cytoskeleton. Minus ends of MTs attach to centrosome (yellow) and plus ends grow radially toward cell periphery. MTs serve as tracks for mobile vesicles, which move from centrosome to cell periphery (red circles) or backwards toward the centrosome (green circles). Reprinted, with permission, from reference .



Figure 8.

Growth and shrinkage of microtubules (MT). Presence of GTP–(α, β)‐tubulin (pink) at the plus end stabilizes the growth phase of MT. GTP hydrolysis results in rapid MT shrinkage, with individual protofilaments bending away from the microtubule axis. The transition from growth to shrinkage is referred to as catastrophe; transition from shrinkage to growth is known as rescue. Reprinted, with permission, from reference .



Figure 9.

Activation of LIM kinase 1 (LIMK1) destabilizes pulmonary interendothelial junctions. (A and B) Electron micrographs of interendothelial junctions (arrows) in WT (A) and limk1–/– mice (B) without and with PAR‐1 peptide agonist as indicated. Magnification, 60,000. (C) Morphometric analysis of open interendothelial junctions induced by exposure of mouse lungs to PAR‐1 agonist. Each bar shows percentage of open junctions out of 50 observations made. PAR‐1 agonist induced significantly more open junctions in WT lungs (P = 0.010197). Error bars represent SEM. Reprinted, with permission, from reference .



Figure 10.

Interendothelial junctions in quiescent cells. (A) Diagram of endothelial adherens junctions and their relationship to actin cytoskeleton. Homotypic adhesion between extracellular domains (EXDS) of VE‐cadherin molecules joins adjacent cells. The juxtramembrane domain (JMD) of VE‐cadherin binds p120 (aqua), a protein regulating the stability of adherens junctions. The carboxyl‐terminal domain (CTD) binds exclusively to either β‐catenin or γ‐catenin (plakoglobin; green), which in turn binds to α‐catenin (dark blue). α‐Catenin interacts with F‐actin directly and indirectly through binding to α‐actinin (light orange) to create a strong link between VE‐cadherin and actin cytoskeleton. Vinculin, another actin‐associated protein, is also depicted (violet). (B) Diagram illustrating endothelial tight junctions. Homotypic adhesion between EXDs of occludin molecules (green) creates the tight junctional contact. The cytoplasmic carboxyl domain of occludin binds to ZO‐1 (red), which is indirectly linked to actin cytoskeleton via α‐catenin (dark blue). Reprinted, with permission, from reference .



Figure 11.

Organization of actin and microtubule cytoskeletons and their relationship to adherens junctions. Monolayer of quiescent human lung microvascular endothelial cells was stained for VE‐cadherin (red), α‐tubulin and actin (green, as indicated), and DNA (blue). Actin organizes into peripheral actin bundles along the VE‐cadherin‐mediated adhesions. Microtubules extend from the centrosome throughout the cell. Image courtesy of Dr.Yulia Komarova.



Figure 12.

Organization of focal adhesions. (A) Immunostaining of endothelial monolayer for actin (green) and focal‐adhesion protein, vinculin (red). (B) Diagram of the focal adhesion complex, showing integrin bound to ECM protein and its intracellular linkage to F‐actin. Image courtesy of Dr. Richard Minshall.



Figure 13.

Receptor control of microvessel permeability. Permeability‐increasing agonist such as thrombin, ligates proteinase‐activated receptor‐1 (PAR‐1), stimulating Gαq and Gα12/13. Gαq triggers increased intracellular Ca2+, which activates EC MLCK (endothelial‐cell myosin light chain kinase) and hence elevates the phosphorylation level of MLC (MLC‐P). Increased intracellular Ca2+ also activates protein kinases, such as PKCα (not shown), which phosphorylate GDI‐1 (GDP‐dissociation inhibitor) and p115RhoGEF (guanine nucleotide exchange factor), thereby increasing the activity of RhoA GTPase. RhoA activates ROCK (rho kinase) and LIMK1 (LIM kinase‐1), which regulates actin binding proteins (cofilin) and thus the state of actin polymerization. ROCK by phosphorylating MLC phosphatase (Ppase) inhibits Ppase and thus increases MLC‐P. Together, these events lead to increased actin‐myosin cross‐bridging, resulting in increased endothelial contraction. Image courtesy of Dr. Dolly Mehta.



Figure 14.

Mechanism of lamellipodia and filopodia formation. (A) Organization of actin cytoskeleton in lamellipodia of fish epidermal keratocytes. Reproduced, with permission, from reference . (B and C) Organization of actin cytoskeleton in filopodia embedded in lamellipodium in B16F1 melanoma cell. (B) Fluorescent image. Region enclosed by rectangle is enlarged in insets. Reproduced, with permission, from reference . (C) Platinum replica EM. Filopodium contains a tight bundle of actin filaments. Inset shows branched actin on surface of lamellipodium. Reproduced, with permission, from reference . (D and E) Model for mechanism of lamellipodial (top) and filopodial (bottom) protrusion depending on capping activity in cells. Top: When capping activity dominates either by activation of CP (capping protein) or inhibition of capping antagonists such as Ena/VASP‐like protein (enabled/ vasodilator‐stimulated phosphoprotein), filaments elongate for a brief period before becoming capped and, as a consequence, these filaments are relatively short. To maintain protrusion, capped filaments are replaced by newly nucleated side branches produced by Arp2/3 complex, favoring the formation of a branching, lamellipodial network. Bottom: Low‐capping activity resulting either from inhibition of CP or activation of proteins that promote anticapping and antibranching such as Ena/VASP, favor filament elongation leading to long and unbranched filaments, which converge and subsequently become bundled by actin cross‐linking molecule, fascin. Filopodia formation is therefore predominant. Modified, with permission, from reference .



Figure 15.

Thrombin‐induced stress fiber formation in endothelial cells (murine lung). Actin is stained in green and nuclei, in blue. Image courtesy of Dr. C. Tiruppathi.



Figure 16.

Intracellular distribution of VE‐cadherin in resting endothelial cells and in cells challenged with pro‐inflammatory mediator, thrombin. Confluent monolayers of HLMVECs, either untreated or treated with 50 nM human α‐thrombin for 30 min, were stained for VE‐cadherin (yellow) and DNA (blue). Thrombin induces disruption of VE‐cadherin‐mediated adhesions and formation of gaps between cells. (Images courtesy of Emily Vandenbroucke).

 1. Abedi H, Zachary I. Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem 272: 15442‐15451, 1997.
 2. Albelda SM, Daise M, Levine EM, Buck CA. Identification and characterization of cell‐substratum adhesion receptors on cultured human endothelial cells. J Clin Invest 83: 1992‐2002, 1989.
 3. Anastasiadis PZ, Reynolds AB. The p120 catenin family: Complex roles in adhesion, signaling and cancer. J Cell Sci 113 (Pt 8): 1319‐1334, 2000.
 4. Anastasiadis PZ, Reynolds AB. Regulation of Rho GTPases by p120‐catenin. Curr Opin Cell Biol 13: 604‐610, 2001.
 5. Ando‐Akatsuka Y, Saitou M, Hirase T, Kishi M, Sakakibara A, Itoh M, Yonemura S, Furuse M, Tsukita S. Interspecies diversity of the occludin sequence: cDNA cloning of human, mouse, dog, and rat‐kangaroo homologues. J Cell Biol 133: 43‐47, 1996.
 6. Andriopoulou P, Navarro P, Zanetti A, Lampugnani MG, Dejana E. Histamine induces tyrosine phosphorylation of endothelial cell‐to‐cell adherens junctions. Arterioscler Thromb Vasc Biol 19: 2286‐2297, 1999.
 7. Anglade D, Corboz M, Menaouar A, Parker JC, Sanou S, Bayat S, Benchetrit G, Grimbert FA. Blood flow vs. venous pressure effects on filtration coefficient in oleic acid‐injured lung. J Appl Physiol 84: 1011‐1023, 1998.
 8. Aramoto H, Breslin JW, Pappas PJ, Hobson RW, 2nd, Duran WN. Vascular endothelial growth factor stimulates differential signaling pathways in in vivo microcirculation. Am J Physiol Heart Circ Physiol 287: H1590‐H1598, 2004.
 9. Arce FT, Whitlock JL, Birukova AA, Birukov KG, Arnsdorf MF, Lal R, Garcia JG, Dudek SM. Regulation of the micromechanical properties of pulmonary endothelium by S1P and thrombin: Role of cortactin. Biophys J 95: 886‐894, 2008.
 10. Aukland K, Reed RK. Interstitial‐lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev 73: 1‐78, 1993.
 11. Aurrand‐Lions M, Johnson‐Leger C, Wong C, Du Pasquier L, Imhof BA. Heterogeneity of endothelial junctions is reflected by differential expression and specific subcellular localization of the three JAM family members. Blood 98: 3699‐3707, 2001.
 12. Aurrand‐Lions MA, Duncan L, Du Pasquier L, Imhof BA. Cloning of JAM‐2 and JAM‐3: An emerging junctional adhesion molecular family? Curr Top Microbiol Immunol 251: 91‐98, 2000.
 13. Axelrad TW, Deo DD, Ottino P, Van Kirk J, Bazan NG, Bazan HE, Hunt JD. Platelet‐activating factor (PAF) induces activation of matrix metalloproteinase 2 activity and vascular endothelial cell invasion and migration. Faseb J 18: 568‐570, 2004.
 14. Bananis E, Murray JW, Stockert RJ, Satir P, Wolkoff AW. Microtubule and motor‐dependent endocytic vesicle sorting in vitro. J Cell Biol 151: 179‐186, 2000.
 15. Bates DO, Curry FE. Vascular endothelial growth factor increases hydraulic conductivity of isolated perfused microvessels. Am J Physiol 271: H2520‐H2528, 1996.
 16. Bates DO, Curry FE. Vascular endothelial growth factor increases microvascular permeability via a Ca(2+)‐dependent pathway. Am J Physiol 273: H687‐H694, 1997.
 17. Bazzoni G, Dejana E. Endothelial cell‐to‐cell junctions: Molecular organization and role in vascular homeostasis. Physiol Rev 84: 869‐901, 2004.
 18. Becker PM, Kazi AA, Wadgaonkar R, Pearse DB, Kwiatkowski D, Garcia JG. Pulmonary vascular permeability and ischemic injury in gelsolin‐deficient mice. Am J Respir Cell Mol Biol 28: 478‐484, 2003.
 19. Becker PM, Verin AD, Booth MA, Liu F, Birukova A, Garcia JG. Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 281: L1500‐L1511, 2001.
 20. Ben‐Ze'ev A, Geiger B. Differential molecular interactions of beta‐catenin and plakoglobin in adhesion, signaling and cancer. Curr Opin Cell Biol 10: 629‐639, 1998.
 21. Ben‐Ze'ev A, Shtutman M, Zhurinsky J. The integration of cell adhesion with gene expression: The role of beta‐catenin. Exp Cell Res 261: 75‐82, 2000.
 22. Bernard O. Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol 39: 1071‐1076, 2007.
 23. Berse B, Brown LF, Van de Water L, Dvorak HF, Senger DR. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 3: 211‐220, 1992.
 24. Bhatt AJ, Amin SB, Chess PR, Watkins RH, Maniscalco WM. Expression of vascular endothelial growth factor and Flk‐1 in developing and glucocorticoid‐treated mouse lung. Pediatr Res 47: 606‐613, 2000.
 25. Birkenfeld J, Nalbant P, Yoon SH, Bokoch GM. Cellular functions of GEF‐H1, a microtubule‐regulated Rho‐GEF: Is altered GEF‐H1 activity a crucial determinant of disease pathogenesis? Trends Cell Biol 18: 210‐219, 2008.
 26. Birukova AA, Birukov KG, Smurova K, Adyshev D, Kaibuchi K, Alieva I, Garcia JG, Verin AD. Novel role of microtubules in thrombin‐induced endothelial barrier dysfunction. Faseb J 18: 1879‐1890, 2004.
 27. Birukova AA, Smurova K, Birukov KG, Usatyuk P, Liu F, Kaibuchi K, Ricks‐Cord A, Natarajan V, Alieva I, Garcia JG, Verin AD. Microtubule disassembly induces cytoskeletal remodeling and lung vascular barrier dysfunction: Role of Rho‐dependent mechanisms. J Cell Physiol 201: 55‐70, 2004.
 28. Bito H, Honda Z, Nakamura M, Shimizu T. Cloning, expression and tissue distribution of rat platelet‐activating‐factor‐receptor cDNA. Eur J Biochem 221: 211‐218, 1994.
 29. Bogatcheva NV, Verin AD. The role of cytoskeleton in the regulation of vascular endothelial barrier function. Microvasc Res 76: 202‐207, 2008.
 30. Breslin JW, Pappas PJ, Cerveira JJ, Hobson RW, 2nd, Duran WN. VEGF increases endothelial permeability by separate signaling pathways involving ERK‐1/2 and nitric oxide. Am J Physiol Heart Circ Physiol 284: H92‐H100, 2003.
 31. Broman MT, Kouklis P, Gao X, Ramchandran R, Neamu RF, Minshall RD, Malik AB. Cdc42 regulates adherens junction stability and endothelial permeability by inducing alpha‐catenin interaction with the vascular endothelial cadherin complex. Circ Res 98: 73‐80, 2006.
 32. Bruns RR, Palade GE. Studies on blood capillaries. I. General organization of blood capillaries in muscle. J Cell Biol 37: 244‐276, 1968.
 33. Bryan BA, D'Amore PA. What tangled webs they weave: Rho‐GTPase control of angiogenesis. Cell Mol Life Sci 64: 2053‐2065, 2007.
 34. Burns AR, Walker DC, Brown ES, Thurmon LT, Bowden RA, Keese CR, Simon SI, Entman ML, Smith CW. Neutrophil transendothelial migration is independent of tight junctions and occurs preferentially at tricellular corners. J Immunol 159: 2893‐2903, 1997.
 35. Burridge K, Fath K, Kelly T, Nuckolls G, Turner C. Focal adhesions: Transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu Rev Cell Biol 4: 487‐525, 1988.
 36. Bussolino F, Camussi G, Aglietta M, Braquet P, Bosia A, Pescarmona G, Sanavio F, D'Urso N, Marchisio PC. Human endothelial cells are target for platelet‐activating factor. I. Platelet‐activating factor induces changes in cytoskeleton structures. J Immunol 139: 2439‐2446, 1987.
 37. Bussolino F, Silvagno F, Garbarino G, Costamagna C, Sanavio F, Arese M, Soldi R, Aglietta M, Pescarmona G, Camussi G, and et al. Human endothelial cells are targets for platelet‐activating factor (PAF). Activation of alpha and beta protein kinase C isozymes in endothelial cells stimulated by PAF. J Biol Chem 269: 2877‐2886, 1994
 38. Carman CV, Sage PT, Sciuto TE, de la Fuente MA, Geha RS, Ochs HD, Dvorak HF, Dvorak AM, Springer TA. Transcellular diapedesis is initiated by invasive podosomes. Immunity 26: 784‐797, 2007.
 39. Carmeliet P, Lampugnani MG, Moons L, Breviario F, Compernolle V, Bono F, Balconi G, Spagnuolo R, Oosthuyse B, Dewerchin M, Zanetti A, Angellilo A, Mattot V, Nuyens D, Lutgens E, Clotman F, de Ruiter MC, Gittenberger‐de Groot A, Poelmann R, Lupu F, Herbert JM, Collen D, Dejana E. Targeted deficiency or cytosolic truncation of the VE‐cadherin gene in mice impairs VEGF‐mediated endothelial survival and angiogenesis. Cell 98: 147‐157, 1999.
 40. Cattelino A, Liebner S, Gallini R, Zanetti A, Balconi G, Corsi A, Bianco P, Wolburg H, Moore R, Oreda B, Kemler R, Dejana E. The conditional inactivation of the beta‐catenin gene in endothelial cells causes a defective vascular pattern and increased vascular fragility. J Cell Biol 162: 1111‐1122, 2003.
 41. Chang L, Goldman RD. Intermediate filaments mediate cytoskeletal crosstalk. Nat Rev Mol Cell Biol 5: 601‐613, 2004.
 42. Chen X, Kojima S, Borisy GG, Green KJ. p120 catenin associates with kinesin and facilitates the transport of cadherin‐catenin complexes to intercellular junctions. J Cell Biol 163: 547‐557, 2003.
 43. Cheng YF, Kramer RH. Human microvascular endothelial cells express integrin‐related complexes that mediate adhesion to the extracellular matrix. J Cell Physiol 139: 275‐286, 1989.
 44. Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar W, Pyne S, Tigyi G. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol Rev 54: 265‐269, 2002.
 45. Cioffi DL, Wu S, Alexeyev M, Goodman SR, Zhu MX, Stevens T. Activation of the endothelial store‐operated ISOC Ca2+ channel requires interaction of protein 4.1 with TRPC4. Circ Res 97: 1164‐1172, 2005.
 46. Conforti G, Zanetti A, Colella S, Abbadini M, Marchisio PC, Pytela R, Giancotti F, Tarone G, Languino LR, Dejana E. Interaction of fibronectin with cultured human endothelial cells: Characterization of the specific receptor. Blood 73: 1576‐1585, 1989.
 47. Cooper JA, Schafer DA. Control of actin assembly and disassembly at filament ends. Curr Opin Cell Biol 12: 97‐103, 2000.
 48. Corada M, Liao F, Lindgren M, Lampugnani MG, Breviario F, Frank R, Muller WA, Hicklin DJ, Bohlen P, Dejana E. Monoclonal antibodies directed to different regions of vascular endothelial cadherin extracellular domain affect adhesion and clustering of the protein and modulate endothelial permeability. Blood 97: 1679‐1684, 2001.
 49. Corada M, Mariotti M, Thurston G, Smith K, Kunkel R, Brockhaus M, Lampugnani MG, Martin‐Padura I, Stoppacciaro A, Ruco L, McDonald DM, Ward PA, Dejana E. Vascular endothelial‐cadherin is an important determinant of microvascular integrity in vivo. Proc Natl Acad Sci U S A 96: 9815‐9820, 1999.
 50. Curtis TM, McKeown‐Longo PJ, Vincent PA, Homan SM, Wheatley EM, Saba TM. Fibronectin attenuates increased endothelial monolayer permeability after RGD peptide, anti‐alpha 5 beta 1, or TNF‐alpha exposure. Am J Physiol 269: L248‐L260, 1995.
 51. De Matteis MA, Morrow JS. Spectrin tethers and mesh in the biosynthetic pathway. J Cell Sci 113 (Pt 13): 2331‐2343, 2000.
 52. Defilippi P, van Hinsbergh V, Bertolotto A, Rossino P, Silengo L, Tarone G. Differential distribution and modulation of expression of alpha 1/beta 1 integrin on human endothelial cells. J Cell Biol 114: 855‐863, 1991.
 53. Dejana E, Colella S, Conforti G, Abbadini M, Gaboli M, Marchisio PC. Fibronectin and vitronectin regulate the organization of their respective Arg‐Gly‐Asp adhesion receptors in cultured human endothelial cells. J Cell Biol 107: 1215‐1223, 1988.
 54. Dejana E, Corada M, Lampugnani MG. Endothelial cell‐to‐cell junctions. Faseb J 9: 910‐918, 1995.
 55. Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE‐cadherin in the control of vascular permeability. J Cell Sci 121: 2115‐2122, 2008.
 56. Dejana E, Orsenigo F, Molendini C, Baluk P, McDonald DM. Organization and signaling of endothelial cell‐to‐cell junctions in various regions of the blood and lymphatic vascular trees. Cell Tissue Res 335: 17‐25, 2009.
 57. Dejana E, Spagnuolo R, Bazzoni G. Interendothelial junctions and their role in the control of angiogenesis, vascular permeability and leukocyte transmigration. Thromb Haemost 86: 308‐315, 2001.
 58. Del Vecchio PJ, Siflinger‐Birnboim A, Belloni PN, Holleran LA, Lum H, Malik AB. Culture and characterization of pulmonary microvascular endothelial cells. In Vitro Cell Dev Biol 28A: 711‐715, 1992.
 59. Dickinson RB. Models for actin polymerization motors. J Math Biol 58: 81‐103, 2009.
 60. dos Remedios CG, Chhabra D, Kekic M, Dedova IV, Tsubakihara M, Berry DA, Nosworthy NJ. Actin binding proteins: Regulation of cytoskeletal microfilaments. Physiol Rev 83: 433‐473, 2003.
 61. Dudek SM, Garcia JG. Cytoskeletal regulation of pulmonary vascular permeability. J Appl Physiol 91: 1487‐1500, 2001.
 62. Dudek SM, Jacobson JR, Chiang ET, Birukov KG, Wang P, Zhan X, Garcia JG. Pulmonary endothelial cell barrier enhancement by sphingosine 1‐phosphate: Roles for cortactin and myosin light chain kinase. J Biol Chem 279: 24692‐24700, 2004.
 63. Dvorak AM, Kohn S, Morgan ES, Fox P, Nagy JA, Dvorak HF. The vesiculo‐vacuolar organelle (VVO): A distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. J Leukoc Biol 59: 100‐115, 1996.
 64. Effros RM. Osmotic extraction of hypotonic fluid from the lungs. J Clin Invest 54: 935‐947, 1974.
 65. Effros RM, Parker JC. Pulmonary vascular heterogeneity and the Starling hypothesis. Microvasc Res 78: 71‐77, 2009.
 66. Effros RM, Schapira R, Presberg K, Ozker K, Jacobs ER. Stop‐flow studies of solute uptake in rat lungs. J Appl Physiol 85: 986‐992, 1998.
 67. Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA. Selective requirement for Src kinases during VEGF‐induced angiogenesis and vascular permeability. Mol Cell 4: 915‐924, 1999.
 68. Engelhardt B, Wolburg H. Mini‐review: Transendothelial migration of leukocytes: Through the front door or around the side of the house? Eur J Immunol 34: 2955‐2963, 2004.
 69. Ermert L, Bruckner H, Walmrath D, Grimminger F, Aktories K, Suttorp N, Duncker HR, Seeger W. Role of endothelial cytoskeleton in high‐permeability edema due to botulinum C2 toxin in perfused rabbit lungs. Am J Physiol 268: L753‐L761, 1995.
 70. Esser S, Lampugnani MG, Corada M, Dejana E, Risau W. Vascular endothelial growth factor induces VE‐cadherin tyrosine phosphorylation in endothelial cells. J Cell Sci 111 (Pt 13): 1853‐1865, 1998.
 71. Essler M, Amano M, Kruse HJ, Kaibuchi K, Weber PC, Aepfelbacher M. Thrombin inactivates myosin light chain phosphatase via Rho and its target Rho kinase in human endothelial cells. J Biol Chem 273: 21867‐21874, 1998.
 72. Essler M, Retzer M, Bauer M, Heemskerk JW, Aepfelbacher M, Siess W. Mildly oxidized low density lipoprotein induces contraction of human endothelial cells through activation of Rho/Rho kinase and inhibition of myosin light chain phosphatase. J Biol Chem 274: 30361‐30364, 1999.
 73. Feng D, Nagy JA, Hipp J, Dvorak HF, Dvorak AM. Vesiculo‐vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin. J Exp Med 183: 1981‐1986, 1996.
 74. Feng D, Nagy JA, Hipp J, Pyne K, Dvorak HF, Dvorak AM. Reinterpretation of endothelial cell gaps induced by vasoactive mediators in guinea‐pig, mouse and rat: Many are transcellular pores. J Physiol 504 (Pt 3): 747‐761, 1997.
 75. Ferrara N, Carver‐Moore K, Chen H, Dowd M, Lu L, O'Shea KS, Powell‐Braxton L, Hillan KJ, Moore MW. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380: 439‐442, 1996.
 76. Form DM, Pratt BM, Madri JA. Endothelial cell proliferation during angiogenesis. In vitro modulation by basement membrane components. Lab Invest 55: 521‐530, 1986.
 77. Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, Buerk DG, Huang PL, Jain RK. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor‐induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A 98: 2604‐2609, 2001.
 78. Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S. Occludin: A novel integral membrane protein localizing at tight junctions. J Cell Biol 123: 1777‐1788, 1993.
 79. Furuse M, Itoh M, Hirase T, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S. Direct association of occludin with ZO‐1 and its possible involvement in the localization of occludin at tight junctions. J Cell Biol 127: 1617‐1626, 1994.
 80. Furuse M, Sasaki H, Tsukita S. Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 147: 891‐903, 1999.
 81. Gamble JR, Drew J, Trezise L, Underwood A, Parsons M, Kasminkas L, Rudge J, Yancopoulos G, Vadas MA. Angiopoietin‐1 is an antipermeability and anti‐inflammatory agent in vitro and targets cell junctions. Circ Res 87: 603‐607, 2000.
 82. Gao X, Kouklis P, Xu N, Minshall RD, Sandoval R, Vogel SM, Malik AB. Reversibility of increased microvessel permeability in response to VE‐cadherin disassembly. Am J Physiol Lung Cell Mol Physiol 279: L1218‐L1225, 2000.
 83. Garcia JG, Davis HW, Patterson CE. Regulation of endothelial cell gap formation and barrier dysfunction: Role of myosin light chain phosphorylation. J Cell Physiol 163: 510‐522, 1995.
 84. Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA, Gerthoffer WT, Bamberg JR, English D. Sphingosine 1‐phosphate promotes endothelial cell barrier integrity by Edg‐dependent cytoskeletal rearrangement. J Clin Invest 108: 689‐701, 2001.
 85. Garcia JG, Schaphorst KL. Regulation of endothelial cell gap formation and paracellular permeability. J Investig Med 43: 117‐126, 1995.
 86. Gavard J, Gutkind JS. VEGF controls endothelial‐cell permeability by promoting the beta‐arrestin‐dependent endocytosis of VE‐cadherin. Nat Cell Biol 8: 1223‐1234, 2006.
 87. Gavard J, Patel V, Gutkind JS. Angiopoietin‐1 prevents VEGF‐induced endothelial permeability by sequestering Src through mDia. Dev Cell 14: 25‐36, 2008.
 88. Gee MH, Williams DO. Effect of lung inflation on perivascular cuff fluid volume in isolated dog lung lobes. Microvasc Res 17: 192‐201, 1979.
 89. Geiger B, Bershadsky A, Pankov R, Yamada KM. Transmembrane crosstalk between the extracellular matrix—cytoskeleton crosstalk. Nat Rev Mol Cell Biol 2: 793‐805, 2001.
 90. Gluecker T, Capasso P, Schnyder P, Gudinchet F, Schaller MD, Revelly JP, Chiolero R, Vock P, Wicky S. Clinical and radiologic features of pulmonary edema. Radiographics 19: 1507‐1531; discussion 1532‐1503, 1999.
 91. Goggel R, Uhlig S. The inositol trisphosphate pathway mediates platelet‐activating‐factor‐induced pulmonary oedema. Eur Respir J 25: 849‐857, 2005.
 92. Gorovoy M, Han J, Pan H, Welch E, Neamu R, Jia Z, Predescu D, Vogel S, Minshall RD, Ye RD, Malik AB, Voyno‐Yasenetskaya T. LIM kinase 1 promotes endothelial barrier disruption and neutrophil infiltration in mouse lungs. Circ Res 105: 549‐556, 2009.
 93. Gorovoy M, Neamu R, Niu J, Vogel S, Predescu D, Miyoshi J, Takai Y, Kini V, Mehta D, Malik AB, Voyno‐Yasenetskaya T. RhoGDI‐1 modulation of the activity of monomeric RhoGTPase RhoA regulates endothelial barrier function in mouse lungs. Circ Res 101: 50‐58, 2007.
 94. Gorovoy M, Niu J, Bernard O, Profirovic J, Minshall R, Neamu R, Voyno‐Yasenetskaya T. LIM kinase 1 coordinates microtubule stability and actin polymerization in human endothelial cells. J Biol Chem 280: 26533‐26542, 2005.
 95. Gory S, Vernet M, Laurent M, Dejana E, Dalmon J, Huber P. The vascular endothelial‐cadherin promoter directs endothelial‐specific expression in transgenic mice. Blood 93: 184‐192, 1999.
 96. Grosheva I, Shtutman M, Elbaum M, Bershadsky AD. p120 catenin affects cell motility via modulation of activity of Rho‐family GTPases: A link between cell‐cell contact formation and regulation of cell locomotion. J Cell Sci 114: 695‐707, 2001.
 97. Grotte G. Passage of dextran molecules across the blood‐lymph barrier. Acta Chir Scand Suppl 211: 1‐84, 1956.
 98. Guo M, Breslin JW, Wu MH, Gottardi CJ, Yuan SY. VE‐cadherin and beta‐catenin binding dynamics during histamine‐induced endothelial hyperpermeability. Am J Physiol Cell Physiol 294: C977‐C984, 2008.
 99. Halonen M, Palmer JD, Lohman IC, McManus LM, Pinckard RN. Respiratory and circulatory alterations induced by acetyl glyceryl ether phosphorylcholine, a mediator of IgE anaphylaxis in the rabbit. Am Rev Respir Dis 122: 915‐924, 1980.
 100. Hamadi A, Bouali M, Dontenwill M, Stoeckel H, Takeda K, Ronde P. Regulation of focal adhesion dynamics and disassembly by phosphorylation of FAK at tyrosine 397. J Cell Sci 118: 4415‐4425, 2005.
 101. Heasman SJ, Ridley AJ. Mammalian Rho GTPases: New insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 9: 690‐701, 2008.
 102. Hirase T, Staddon JM, Saitou M, Ando‐Akatsuka Y, Itoh M, Furuse M, Fujimoto K, Tsukita S, Rubin LL. Occludin as a possible determinant of tight junction permeability in endothelial cells. J Cell Sci 110 (Pt 14): 1603‐1613, 1997.
 103. Hla T. Signaling and biological actions of sphingosine 1‐phosphate. Pharmacol Res 47: 401‐407, 2003.
 104. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397: 259‐263, 1999.
 105. Holinstat M, Knezevic N, Broman M, Samarel AM, Malik AB, Mehta D. Suppression of RhoA activity by focal adhesion kinase‐induced activation of p190RhoGAP: Role in regulation of endothelial permeability. J Biol Chem 281: 2296‐2305, 2006.
 106. Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB. Protein kinase Calpha‐induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement. J Biol Chem 278: 28793‐28798, 2003.
 107. Hotulainen P, Lappalainen P. Stress fibers are generated by two distinct actin assembly mechanisms in motile cells. J Cell Biol 173: 383‐394, 2006.
 108. Howard J, Hyman AA. Dynamics and mechanics of the microtubule plus end. Nature 422: 753‐758, 2003.
 109. Howard J, Hyman AA. Growth, fluctuation and switching at microtubule plus ends. Nat Rev Mol Cell Biol 10: 569‐574, 2009.
 110. Huber AH, Weis WI. The structure of the beta‐catenin/E‐cadherin complex and the molecular basis of diverse ligand recognition by beta‐catenin. Cell 105: 391‐402, 2001.
 111. Hudry‐Clergeon H, Stengel D, Ninio E, Vilgrain I. Platelet‐activating factor increases VE‐cadherin tyrosine phosphorylation in mouse endothelial cells and its association with the PtdIns3′‐kinase. Faseb J 19: 512‐520, 2005.
 112. Hynes RO. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 69: 11‐25, 1992.
 113. Imamura Y, Itoh M, Maeno Y, Tsukita S, Nagafuchi A. Functional domains of alpha‐catenin required for the strong state of cadherin‐based cell adhesion. J Cell Biol 144: 1311‐1322, 1999.
 114. Ingber DE. Cellular tensegrity: Defining new rules of biological design that govern the cytoskeleton. J Cell Sci 104 (Pt 3): 613‐627, 1993.
 115. Ingber DE. Tensegrity I. Cell structure and hierarchical systems biology. J Cell Sci 116: 1157‐1173, 2003.
 116. Itoh M, Nagafuchi A, Yonemura S, Kitani‐Yasuda T, Tsukita S, Tsukita S. The 220‐kD protein colocalizing with cadherins in non‐epithelial cells is identical to ZO‐1, a tight junction‐associated protein in epithelial cells: cDNA cloning and immunoelectron microscopy. J Cell Biol 121: 491‐502, 1993.
 117. Ivetic A, Ridley AJ. Ezrin/radixin/moesin proteins and Rho GTPase signalling in leucocytes. Immunology 112: 165‐176, 2004.
 118. Iyer S, Ferreri DM, DeCocco NC, Minnear FL, Vincent PA. VE‐cadherin‐p120 interaction is required for maintenance of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol 286: L1143‐L1153, 2004.
 119. Jho D, Mehta D, Ahmmed G, Gao XP, Tiruppathi C, Broman M, Malik AB. Angiopoietin‐1 opposes VEGF‐induced increase in endothelial permeability by inhibiting TRPC1‐dependent Ca2 influx. Circ Res 96: 1282‐1290, 2005.
 120. Jiang Y, Wen K, Zhou X, Schwegler‐Berry D, Castranova V, He P. Three‐dimensional localization and quantification of PAF‐induced gap formation in intact venular microvessels. Am J Physiol Heart Circ Physiol 295: H898‐H906, 2008.
 121. Johansson BR. Size and distribution of endothelial plasmalemmal vesicles in consecutive segments of the microvasculature in cat skeletal muscle. Microvasc Res 17: 107‐117, 1979.
 122. Jones N, Iljin K, Dumont DJ, Alitalo K. Tie receptors: New modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2: 257‐267, 2001.
 123. Kaner RJ, Crystal RG. Compartmentalization of vascular endothelial growth factor to the epithelial surface of the human lung. Mol Med 7: 240‐246, 2001.
 124. Kaner RJ, Ladetto JV, Singh R, Fukuda N, Matthay MA, Crystal RG. Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema. Am J Respir Cell Mol Biol 22: 657‐664, 2000.
 125. Karakozova M, Kozak M, Wong CC, Bailey AO, Yates JR, 3rd, Mogilner A, Zebroski H, Kashina A. Arginylation of beta‐actin regulates actin cytoskeleton and cell motility. Science 313: 192‐196, 2006.
 126. Kedem O, Katchalsky A. Thermodynamic analysis of the permeability of biological membranes to non‐electrolytes. Biochim Biophys Acta 27: 229‐246, 1958.
 127. Kelly JJ, Moore TM, Babal P, Diwan AH, Stevens T, Thompson WJ. Pulmonary microvascular and macrovascular endothelial cells: Differential regulation of Ca2+ and permeability. Am J Physiol 274: L810‐L819, 1998.
 128. Kern DF, Malik AB. Microvascular albumin permeability in isolated perfused lung: Effects of EDTA. J Appl Physiol 58: 372‐375, 1985.
 129. Kevil CG, Okayama N, Trocha SD, Kalogeris TJ, Coe LL, Specian RD, Davis CP, Alexander JS. Expression of zonula occludens and adherens junctional proteins in human venous and arterial endothelial cells: Role of occludin in endothelial solute barriers. Microcirculation 5: 197‐210, 1998.
 130. Kevil CG, Payne DK, Mire E, Alexander JS. Vascular permeability factor/vascular endothelial cell growth factor‐mediated permeability occurs through disorganization of endothelial junctional proteins. J Biol Chem 273: 15099‐15103, 1998.
 131. Klein IK, Predescu DN, Sharma T, Knezevic I, Malik AB, Predescu S. Intersectin‐2L regulates caveola endocytosis secondary to Cdc42‐mediated actin polymerization. J Biol Chem 284: 25953‐25961, 2009.
 132. Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS. Continuous low‐dose therapy with vinblastine and VEGF receptor‐2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105: R15‐R24, 2000.
 133. Knezevic, II, Predescu SA, Neamu RF, Gorovoy MS, Knezevic NM, Easington C, Malik AB, Predescu DN. Tiam1 and Rac1 are required for platelet‐activating factor‐induced endothelial junctional disassembly and increase in vascular permeability. J Biol Chem 284: 5381‐5394, 2009.
 134. Knezevic N, Roy A, Timblin B, Konstantoulaki M, Sharma T, Malik AB, Mehta D. GDI‐1 phosphorylation switch at serine 96 induces RhoA activation and increased endothelial permeability. Mol Cell Biol 27: 6323‐6333, 2007.
 135. Knezevic N, Tauseef M, Thennes T, Mehta D. The G protein betagamma subunit mediates reannealing of adherens junctions to reverse endothelial permeability increase by thrombin. J Exp Med 206: 2761‐2777, 2009.
 136. Knudsen KA, Soler AP, Johnson KR, Wheelock MJ. Interaction of alpha‐actinin with the cadherin/catenin cell‐cell adhesion complex via alpha‐catenin. J Cell Biol 130: 67‐77, 1995.
 137. Kobielak A, Pasolli HA, Fuchs E. Mammalian formin‐1 participates in adherens junctions and polymerization of linear actin cables. Nat Cell Biol 6: 21‐30, 2004.
 138. Kouklis P, Konstantoulaki M, Malik AB. VE‐cadherin‐induced Cdc42 signaling regulates formation of membrane protrusions in endothelial cells. J Biol Chem 278: 16230‐16236, 2003.
 139. Kouklis P, Konstantoulaki M, Vogel S, Broman M, Malik AB. Cdc42 regulates the restoration of endothelial barrier function. Circ Res 94: 159‐166, 2004.
 140. Kozasa T, Jiang X, Hart MJ, Sternweis PM, Singer WD, Gilman AG, Bollag G, Sternweis PC. p115 RhoGEF, a GTPase activating protein for Galpha12 and Galpha13. Science 280: 2109‐2111, 1998.
 141. Kueh HY, Mitchison TJ. Structural plasticity in actin and tubulin polymer dynamics. Science 325: 960‐963, 2009.
 142. Lal BK, Varma S, Pappas PJ, Hobson RW, 2nd, Duran WN. VEGF increases permeability of the endothelial cell monolayer by activation of PKB/akt, endothelial nitric‐oxide synthase, and MAP kinase pathways. Microvasc Res 62: 252‐262, 2001.
 143. Lamb JA, Allen PG, Tuan BY, Janmey PA. Modulation of gelsolin function. Activation at low pH overrides Ca2+ requirement. J Biol Chem 268: 8999‐9004, 1993.
 144. Lampugnani MG, Resnati M, Dejana E, Marchisio PC. The role of integrins in the maintenance of endothelial monolayer integrity. J Cell Biol 112: 479‐490, 1991.
 145. Lampugnani MG, Resnati M, Raiteri M, Pigott R, Pisacane A, Houen G, Ruco LP, Dejana E. A novel endothelial‐specific membrane protein is a marker of cell‐cell contacts. J Cell Biol 118: 1511‐1522, 1992.
 146. Lawler J, Hynes RO. An integrin receptor on normal and thrombasthenic platelets that binds thrombospondin. Blood 74: 2022‐2027, 1989.
 147. Lee JS, Gotlieb AI. Microtubule‐actin interactions may regulate endothelial integrity and repair. Cardiovasc Pathol 11: 135‐140, 2002.
 148. Lee MJ, Thangada S, Claffey KP, Ancellin N, Liu CH, Kluk M, Volpi M, Sha'afi RI, Hla T. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine‐1‐phosphate. Cell 99: 301‐312, 1999.
 149. Lee TY, Gotlieb AI. Microfilaments and microtubules maintain endothelial integrity. Microsc Res Tech 60: 115‐127, 2003.
 150. Lemonnier L, Trebak M, Putney JW, Jr. Complex regulation of the TRPC3, 6 and 7 channel subfamily by diacylglycerol and phosphatidylinositol‐4,5‐bisphosphate. Cell Calcium 43: 506‐514, 2008.
 151. Leu NA, Kurosaka S, Kashina A. Conditional Tek promoter‐driven deletion of arginyltransferase in the germ line causes defects in gametogenesis and early embryonic lethality in mice. PLoS One 4: e7734, 2009.
 152. Liaw CW, Cannon C, Power MD, Kiboneka PK, Rubin LL. Identification and cloning of two species of cadherins in bovine endothelial cells. Embo J 9: 2701‐2708, 1990.
 153. Loo DT, Kanner SB, Aruffo A. Filamin binds to the cytoplasmic domain of the beta1‐integrin. Identification of amino acids responsible for this interaction. J Biol Chem 273: 23304‐23312, 1998.
 154. Lossinsky AS, Shivers RR. Structural pathways for macromolecular and cellular transport across the blood‐brain barrier during inflammatory conditions. Review. Histol Histopathol 19: 535‐564, 2004.
 155. Lum H, Malik AB. Regulation of vascular endothelial barrier function. Am J Physiol 267: L223‐L241, 1994.
 156. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM‐kinase. Science 285: 895‐898, 1999.
 157. Majno G, Palade GE. Studies on inflammation. 1. The effect of histamine and serotonin on vascular permeability: An electron microscopic study. J Biophys Biochem Cytol 11: 571‐605, 1961.
 158. Malik AB, Vogel, SM, Minshall, RD, Tiruppathi, C. Pulmonary Circulation and Regulation of Fluid Balance. In: Murray JFaN, JA, editor. Textbook of Respiratory Medicine. Philadelphia, PA: W.B. Saunders Co., 2000, p. 119‐154.
 159. Maniscalco WM, Watkins RH, Finkelstein JN, Campbell MH. Vascular endothelial growth factor mRNA increases in alveolar epithelial cells during recovery from oxygen injury. Am J Respir Cell Mol Biol 13: 377‐386, 1995.
 160. Matthay MA, Zimmerman GA. Acute lung injury and the acute respiratory distress syndrome: Four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33: 319‐327, 2005.
 161. McDonald DM. Endothelial gaps and permeability of venules in rat tracheas exposed to inflammatory stimuli. Am J Physiol 266: L61‐L83, 1994.
 162. McVerry BJ, Garcia JG. Endothelial cell barrier regulation by sphingosine 1‐phosphate. J Cell Biochem 92: 1075‐1085, 2004.
 163. McVerry BJ, Garcia JG. In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1‐phosphate: Mechanistic insights. Cell Signal 17: 131‐139, 2005.
 164. McVerry BJ, Peng X, Hassoun PM, Sammani S, Simon BA, Garcia JG. Sphingosine 1‐phosphate reduces vascular leak in murine and canine models of acute lung injury. Am J Respir Crit Care Med 170: 987‐993, 2004.
 165. Mechtersheimer G, Barth T, Quentmeier A, Moller P. Differential expression of beta 1, beta 3, and beta 4 integrin subunits in nonneoplastic neural cells of the peripheral and autonomic nervous system and in tumors derived from these cells. Lab Invest 70: 740‐752, 1994.
 166. Mehta D, Ahmmed GU, Paria BC, Holinstat M, Voyno‐Yasenetskaya T, Tiruppathi C, Minshall RD, Malik AB. RhoA interaction with inositol 1,4,5‐trisphosphate receptor and transient receptor potential channel‐1 regulates Ca2+ entry. Role in signaling increased endothelial permeability. J Biol Chem 278: 33492‐33500, 2003.
 167. Mehta D, Konstantoulaki M, Ahmmed GU, Malik AB. Sphingosine 1‐phosphate‐induced mobilization of intracellular Ca2+ mediates rac activation and adherens junction assembly in endothelial cells. J Biol Chem 280: 17320‐17328, 2005.
 168. Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability. Physiol Rev 86: 279‐367, 2006.
 169. Mehta D, Rahman A, Malik AB. Protein kinase C‐alpha signals rho‐guanine nucleotide dissociation inhibitor phosphorylation and rho activation and regulates the endothelial cell barrier function. J Biol Chem 276: 22614‐22620, 2001.
 170. Mehta D, Tiruppathi C, Sandoval R, Minshall RD, Holinstat M, Malik AB. Modulatory role of focal adhesion kinase in regulating human pulmonary arterial endothelial barrier function. J Physiol 539: 779‐789, 2002.
 171. Mejillano MR, Kojima S, Applewhite DA, Gertler FB, Svitkina TM, Borisy GG. Lamellipodial versus filopodial mode of the actin nanomachinery: Pivotal role of the filament barbed end. Cell 118: 363‐373, 2004.
 172. Melnikova V, Bar‐Eli M. Inflammation and melanoma growth and metastasis: The role of platelet‐activating factor (PAF) and its receptor. Cancer Metastasis Rev 26: 359‐371, 2007.
 173. Michel CC. Transport of macromolecules through microvascular walls. Cardiovasc Res 32: 644‐653, 1996.
 174. Michel CC, Curry FE. Microvascular permeability. Physiol Rev 79: 703‐761, 1999.
 175. Michel CC, Neal CR. Openings through endothelial cells associated with increased microvascular permeability. Microcirculation 6: 45‐54, 1999.
 176. Millan J, Hewlett L, Glyn M, Toomre D, Clark P, Ridley AJ. Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM‐1 to caveola‐ and F‐actin‐rich domains. Nat Cell Biol 8: 113‐123, 2006.
 177. Millard TH, Sharp SJ, Machesky LM. Signalling to actin assembly via the WASP (Wiskott‐Aldrich syndrome protein)‐family proteins and the Arp2/3 complex. Biochem J 380: 1‐17, 2004.
 178. Minshall RD, Tiruppathi C, Vogel SM, Malik AB. Vesicle formation and trafficking in endothelial cells and regulation of endothelial barrier function. Histochem Cell Biol 117: 105‐112, 2002.
 179. Miron T, Vancompernolle K, Vandekerckhove J, Wilchek M, Geiger B. A 25‐kD inhibitor of actin polymerization is a low molecular mass heat shock protein. J Cell Biol 114: 255‐261, 1991.
 180. Miserocchi G, Negrini D, Gonano C. Direct measurement of interstitial pulmonary pressure in in situ lung with intact pleural space. J Appl Physiol 69: 2168‐2174, 1990.
 181. Miserocchi G, Negrini D, Gonano C. Parenchymal stress affects interstitial and pleural pressures in in situ lung. J Appl Physiol 71: 1967‐1972, 1991.
 182. Monacci WT, Merrill MJ, Oldfield EH. Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol 264: C995‐C1002, 1993.
 183. Morita K, Sasaki H, Furuse M, Tsukita S. Endothelial claudin: Claudin‐5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol 147: 185‐194, 1999.
 184. Moritz M, Braunfeld MB, Guenebaut V, Heuser J, Agard DA. Structure of the gamma‐tubulin ring complex: A template for microtubule nucleation. Nat Cell Biol 2: 365‐370, 2000.
 185. Moy AB, Winter M, Kamath A, Blackwell K, Reyes G, Giaever I, Keese C, Shasby DM. Histamine alters endothelial barrier function at cell‐cell and cell‐matrix sites. Am J Physiol Lung Cell Mol Physiol 278: L888‐L898, 2000.
 186. Muller SL, Portwich M, Schmidt A, Utepbergenov DI, Huber O, Blasig IE, Krause G. The tight junction protein occludin and the adherens junction protein alpha‐catenin share a common interaction mechanism with ZO‐1. J Biol Chem 280: 3747‐3756, 2005.
 187. Muller WA. Leukocyte‐endothelial‐cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 24: 327‐334, 2003.
 188. Nakamura M, Honda Z, Izumi T, Sakanaka C, Mutoh H, Minami M, Bito H, Seyama Y, Matsumoto T, Noma M, and et al. Molecular cloning and expression of platelet‐activating factor receptor from human leukocytes. J Biol Chem 266: 20400‐20405, 1991.
 189. Navarro P, Caveda L, Breviario F, Mandoteanu I, Lampugnani MG, Dejana E. Catenin‐dependent and ‐independent functions of vascular endothelial cadherin. J Biol Chem 270: 30965‐30972, 1995.
 190. Negrini D, Gonano C, Miserocchi G. Microvascular pressure profile in intact in situ lung. J Appl Physiol 72: 332‐339, 1992.
 191. Negrini D, Passi A. Interstitial matrix and transendothelial fluxes in normal lung. Respir Physiol Neurobiol 159: 301‐310, 2007.
 192. Negrini D, Passi A, Bertin K, Bosi F, Wiig H. Isolation of pulmonary interstitial fluid in rabbits by a modified wick technique. Am J Physiol Lung Cell Mol Physiol 280: L1057‐L1065, 2001.
 193. Nieset JE, Redfield AR, Jin F, Knudsen KA, Johnson KR, Wheelock MJ. Characterization of the interactions of alpha‐catenin with alpha‐actinin and beta‐catenin/plakoglobin. J Cell Sci 110 (Pt 8): 1013‐1022, 1997.
 194. Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S. Size‐selective loosening of the blood‐brain barrier in claudin‐5‐deficient mice. J Cell Biol 161: 653‐660, 2003.
 195. Noren NK, Liu BP, Burridge K, Kreft B. p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J Cell Biol 150: 567‐580, 2000.
 196. Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S, Mizuno K. Rho‐associated kinase ROCK activates LIM‐kinase 1 by phosphorylation at threonine 508 within the activation loop. J Biol Chem 275: 3577‐3582, 2000.
 197. Orrington‐Myers J, Gao X, Kouklis P, Broman M, Rahman A, Vogel SM, Malik AB. Regulation of lung neutrophil recruitment by VE‐cadherin. Am J Physiol Lung Cell Mol Physiol 291: L764‐L771, 2006.
 198. Ozawa M, Ringwald M, Kemler R. Uvomorulin‐catenin complex formation is regulated by a specific domain in the cytoplasmic region of the cell adhesion molecule. Proc Natl Acad Sci U S A 87: 4246‐4250, 1990.
 199. Palade GE. An electron microscope study of the mitochondrial structure. J Histochem Cytochem 1: 188‐211, 1953.
 200. Papadopoulos MC, Saadoun S, Verkman AS. Aquaporins and cell migration. Pflugers Arch 456: 693‐700, 2008.
 201. Pappenheimer JR, Renkin EM, Borrero LM. Filtration, diffusion and molecular sieving through peripheral capillary membranes; a contribution to the pore theory of capillary permeability. Am J Physiol 167: 13‐46, 1951.
 202. Parker JC. Hydraulic conductance of lung endothelial phenotypes and Starling safety factors against edema. Am J Physiol Lung Cell Mol Physiol 292: L378‐L380, 2007.
 203. Parker JC, Yoshikawa S. Vascular segmental permeabilities at high peak inflation pressure in isolated rat lungs. Am J Physiol Lung Cell Mol Physiol 283: L1203‐L1209, 2002.
 204. Patterson CE, Lum H. Update on pulmonary edema: The role and regulation of endothelial barrier function. Endothelium 8: 75‐105, 2001.
 205. Patton WF, Yoon MU, Alexander JS, Chung‐Welch N, Hechtman HB, Shepro D. Expression of simple epithelial cytokeratins in bovine pulmonary microvascular endothelial cells. J Cell Physiol 143: 140‐149, 1990.
 206. Peng X, Hassoun PM, Sammani S, McVerry BJ, Burne MJ, Rabb H, Pearse D, Tuder RM, Garcia JG. Protective effects of sphingosine 1‐phosphate in murine endotoxin‐induced inflammatory lung injury. Am J Respir Crit Care Med 169: 1245‐1251, 2004.
 207. Phillips PG, Lum H, Malik AB, Tsan MF. Phallacidin prevents thrombin‐induced increases in endothelial permeability to albumin. Am J Physiol 257: C562‐C567, 1989.
 208. Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7: 803‐815, 2007.
 209. Pocock TM, Bates DO. In vivo mechanisms of vascular endothelial growth factor‐mediated increased hydraulic conductivity of Rana capillaries. J Physiol 534: 479‐488, 2001.
 210. Pocock TM, Foster RR, Bates DO. Evidence of a role for TRPC channels in VEGF‐mediated increased vascular permeability in vivo. Am J Physiol Heart Circ Physiol 286: H1015‐H1026, 2004.
 211. Pocock TM, Williams B, Curry FE, Bates DO. VEGF and ATP act by different mechanisms to increase microvascular permeability and endothelial [Ca(2+)](i). Am J Physiol Heart Circ Physiol 279: H1625‐H1634, 2000.
 212. Pollard TD, Borisy GG. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112: 453‐465, 2003.
 213. Prasain N, Stevens T. The actin cytoskeleton in endothelial cell phenotypes. Microvasc Res 77: 53‐63, 2009.
 214. Predescu D, Horvat R, Predescu S, Palade GE. Transcytosis in the continuous endothelium of the myocardial microvasculature is inhibited by N‐ethylmaleimide. Proc Natl Acad Sci U S A 91: 3014‐3018, 1994.
 215. Predescu D, Palade GE. Plasmalemmal vesicles represent the large pore system of continuous microvascular endothelium. Am J Physiol 265: H725‐H733, 1993.
 216. Predescu D, Predescu S, McQuistan T, Palade GE. Transcytosis of alpha1‐acidic glycoprotein in the continuous microvascular endothelium. Proc Natl Acad Sci U S A 95: 6175‐6180, 1998.
 217. Predescu D, Vogel SM, Malik AB. Functional and morphological studies of protein transcytosis in continuous endothelia. Am J Physiol Lung Cell Mol Physiol 287: L895‐L901, 2004.
 218. Predescu SA, Predescu DN, Malik AB. Molecular determinants of endothelial transcytosis and their role in endothelial permeability. Am J Physiol Lung Cell Mol Physiol 293: L823‐L842, 2007.
 219. Predescu SA, Predescu DN, Palade GE. Plasmalemmal vesicles function as transcytotic carriers for small proteins in the continuous endothelium. Am J Physiol 272: H937‐H949, 1997.
 220. Prussin C, Metcalfe DD. 4. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 111: S486‐S494, 2003.
 221. Qiao RL, Wang HS, Yan W, Odekon LE, Del Vecchio PJ, Smith TJ, Malik AB. Extracellular matrix hyaluronan is a determinant of the endothelial barrier. Am J Physiol 269: C103‐C109, 1995.
 222. Ramchandran R, Mehta D, Vogel SM, Mirza MK, Kouklis P, Malik AB. Critical role of Cdc42 in mediating endothelial barrier protection in vivo. Am J Physiol Lung Cell Mol Physiol 295: L363‐L369, 2008.
 223. Revenu C, Athman R, Robine S, Louvard D. The co‐workers of actin filaments: From cell structures to signals. Nat Rev Mol Cell Biol 5: 635‐646, 2004.
 224. Ridley AJ. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol 16: 522‐529, 2006.
 225. Rippe B, Haraldsson B. Transport of macromolecules across microvascular walls: The two‐pore theory. Physiol Rev 74: 163‐219, 1994.
 226. Roberts WG, Palade GE. Endothelial fenestrae and fenestral diaphragms. In: Risau W, Rubanyi GM, editors. Morphogenesis of Endothelium. Amsterdam: Harwood Academic, 2000, p. 23‐41.
 227. Rosales C, Gresham HD, Brown EJ. Expression of the 50‐kDa integrin‐associated protein on myeloid cells and erythrocytes. J Immunol 149: 2759‐2764, 1992.
 228. Rosen H, Gonzalez‐Cabrera PJ, Sanna MG, Brown S. Sphingosine 1‐phosphate receptor signaling. Annu Rev Biochem 78: 743‐768, 2009.
 229. Rotundo RF, Curtis TM, Shah MD, Gao B, Mastrangelo A, LaFlamme SE, Saba TM. TNF‐alpha disruption of lung endothelial integrity: Reduced integrin mediated adhesion to fibronectin. Am J Physiol Lung Cell Mol Physiol 282: L316‐L329, 2002.
 230. Roura S, Miravet S, Piedra J, Garcia de Herreros A, Dunach M. Regulation of E‐cadherin/Catenin association by tyrosine phosphorylation. J Biol Chem 274: 36734‐36740, 1999.
 231. Rutili G, Kvietys P, Martin D, Parker JC, Taylor AE. Increased pulmonary microvasuclar permeability induced by alpha‐naphthylthiourea. J Appl Physiol 52: 1316‐1323, 1982.
 232. Saitou M, Furuse M, Sasaki H, Schulzke JD, Fromm M, Takano H, Noda T, Tsukita S. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell 11: 4131‐4142, 2000.
 233. Sanchez T, Estrada‐Hernandez T, Paik JH, Wu MT, Venkataraman K, Brinkmann V, Claffey K, Hla T. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor‐induced vascular permeability. J Biol Chem 278: 47281‐47290, 2003.
 234. Schaphorst KL, Chiang E, Jacobs KN, Zaiman A, Natarajan V, Wigley F, Garcia JG. Role of sphingosine‐1 phosphate in the enhancement of endothelial barrier integrity by platelet‐released products. Am J Physiol Lung Cell Mol Physiol 285: L258‐L267, 2003.
 235. Schaub S, Bohnet S, Laurent VM, Meister JJ, Verkhovsky AB. Comparative maps of motion and assembly of filamentous actin and myosin II in migrating cells. Mol Biol Cell 18: 3723‐3732, 2007.
 236. Schlaepfer DD, Mitra SK. Multiple connections link FAK to cell motility and invasion. Curr Opin Genet Dev 14: 92‐101, 2004.
 237. Schmidt A, Utepbergenov DI, Mueller SL, Beyermann M, Schneider‐Mergener J, Krause G, Blasig IE. Occludin binds to the SH3‐hinge‐GuK unit of zonula occludens protein 1: Potential mechanism of tight junction regulation. Cell Mol Life Sci 61: 1354‐1365, 2004.
 238. Schneeberger EE. Structure of intercellular junctions in different segments of the intrapulmonary vasculature. Ann N Y Acad Sci 384: 54‐63, 1982.
 239. Schnittler HJ. Structural and functional aspects of intercellular junctions in vascular endothelium. Basic Res Cardiol 93 Suppl 3: 30‐39, 1998.
 240. Schnitzer JE. gp60 is an albumin‐binding glycoprotein expressed by continuous endothelium involved in albumin transcytosis. Am J Physiol 262: H246‐H254, 1992.
 241. Schnitzer JE, Oh P. Albondin‐mediated capillary permeability to albumin. Differential role of receptors in endothelial transcytosis and endocytosis of native and modified albumins. J Biol Chem 269: 6072‐6082, 1994.
 242. Sharma CP, Ezzell RM, Arnaout MA. Direct interaction of filamin (ABP‐280) with the beta 2‐integrin subunit CD18. J Immunol 154: 3461‐3470, 1995.
 243. Shasby DM. Cell‐cell adhesion in lung endothelium. Am J Physiol Lung Cell Mol Physiol 292: L593‐L607, 2007.
 244. Shasby DM, Ries DR, Shasby SS, Winter MC. Histamine stimulates phosphorylation of adherens junction proteins and alters their link to vimentin. Am J Physiol Lung Cell Mol Physiol 282: L1330‐L1338, 2002.
 245. Shasby DM, Shasby SS, Sullivan JM, Peach MJ. Role of endothelial cell cytoskeleton in control of endothelial permeability. Circ Res 51: 657‐661, 1982.
 246. Shen TL, Park AY, Alcaraz A, Peng X, Jang I, Koni P, Flavell RA, Gu H, Guan JL. Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. J Cell Biol 169: 941‐952, 2005.
 247. Shikata Y, Birukov KG, Birukova AA, Verin A, Garcia JG. Involvement of site‐specific FAK phosphorylation in sphingosine‐1 phosphate‐ and thrombin‐induced focal adhesion remodeling: Role of Src and GIT. Faseb J 17: 2240‐2249, 2003.
 248. Siflinger‐Birnboim A, Cooper JA, del Vecchio PJ, Lum H, Malik AB. Selectivity of the endothelial monolayer: Effects of increased permeability. Microvasc Res 36: 216‐227, 1988.
 249. Simionescu M. Structural, biochemical and functional differentiation of the vascular endothelium. In: Risau W, Rubanyi GM, editors, Morphogenesis of Endothelium. Amsterdam: Harwood Academic, 2000, p. 1‐21.
 250. Simons PC, Pietromonaco SF, Reczek D, Bretscher A, Elias L. C‐terminal threonine phosphorylation activates ERM proteins to link the cell's cortical lipid bilayer to the cytoskeleton. Biochem Biophys Res Commun 253: 561‐565, 1998.
 251. Singleton PA, Dudek SM, Chiang ET, Garcia JG. Regulation of sphingosine 1‐phosphate‐induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and alpha‐actinin. Faseb J 19: 1646‐1656, 2005.
 252. Small JV, Stradal T, Vignal E, Rottner K. The lamellipodium: Where motility begins. Trends Cell Biol 12: 112‐120, 2002.
 253. Smith JW, Cheresh DA. Integrin (alpha v beta 3)‐ligand interaction. Identification of a heterodimeric RGD binding site on the vitronectin receptor. J Biol Chem 265: 2168‐2172, 1990.
 254. Starling EH. On the absorption of fluids from the connective tissue spaces. J Physiol 19: 312‐326, 1896.
 255. Staub NC, Gee M, Vreim C. Mechanism of alveolar flooding in acute pulmonary oedema. Ciba Found Symp 255‐272, 1976.
 256. Stevens T, Garcia JG, Shasby DM, Bhattacharya J, Malik AB. Mechanisms regulating endothelial cell barrier function. Am J Physiol Lung Cell Mol Physiol 279: L419‐L422, 2000.
 257. Stickel SK, Wang YL. Synthetic peptide GRGDS induces dissociation of alpha‐actinin and vinculin from the sites of focal contacts. J Cell Biol 107: 1231‐1239, 1988.
 258. Strelkov SV, Herrmann H, Aebi U. Molecular architecture of intermediate filaments. Bioessays 25: 243‐251, 2003.
 259. Sun H, Breslin JW, Zhu J, Yuan SY, Wu MH. Rho and ROCK signaling in VEGF‐induced microvascular endothelial hyperpermeability. Microcirculation 13: 237‐247, 2006.
 260. Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD. Requisite role of angiopoietin‐1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87: 1171‐1180, 1996.
 261. Svitkina TM, Bulanova EA, Chaga OY, Vignjevic DM, Kojima S, Vasiliev JM, Borisy GG. Mechanism of filopodia initiation by reorganization of a dendritic network. J Cell Biol 160: 409‐421, 2003.
 262. Taddei A, Giampietro C, Conti A, Orsenigo F, Breviario F, Pirazzoli V, Potente M, Daly C, Dimmeler S, Dejana E. Endothelial adherens junctions control tight junctions by VE‐cadherin‐mediated upregulation of claudin‐5. Nat Cell Biol 10: 923‐934, 2008.
 263. Takahashi K, Sasaki T, Mammoto A, Takaishi K, Kameyama T, Tsukita S, Takai Y. Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J Biol Chem 272: 23371‐23375, 1997.
 264. Tarone G, Stefanuto G, Mascarello P, Defilippi P, Altruda F, Silengo L. Expression of receptors for extracellular matrix proteins in human endothelial cells. J Lipid Mediat 2 Suppl: S45‐S53, 1990.
 265. Tauseef M, Kini V, Knezevic N, Brannan M, Ramchandaran R, Fyrst H, Saba J, Vogel SM, Malik AB, Mehta D. Activation of sphingosine kinase‐1 reverses the increase in lung vascular permeability through sphingosine‐1‐phosphate receptor signaling in endothelial cells. Circ Res 103: 1164‐1172, 2008.
 266. Taylor AE, Parker JC. Pulmonary interstitial space and lymphatics. In: Fishman AP, Fisher AB, editors. Handbook of Physiology The Respiratory System Circulations and Non‐respiratory Functions, Bethesda, MD: The American Physiological Society, 1985, chapt 4, p. 167‐230.
 267. Thoreson MA, Anastasiadis PZ, Daniel JM, Ireton RC, Wheelock MJ, Johnson KR, Hummingbird DK, Reynolds AB. Selective uncoupling of p120(ctn) from E‐cadherin disrupts strong adhesion. J Cell Biol 148: 189‐202, 2000.
 268. Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD. Angiopoietin‐1 protects the adult vasculature against plasma leakage. Nat Med 6: 460‐463, 2000.
 269. Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM. Leakage‐resistant blood vessels in mice transgenically overexpressing angiopoietin‐1. Science 286: 2511‐2514, 1999.
 270. Tiruppathi C, Finnegan A, Malik AB. Isolation and characterization of a cell surface albumin‐binding protein from vascular endothelial cells. Proc Natl Acad Sci U S A 93: 250‐254, 1996.
 271. Tiruppathi C, Malik AB, Del Vecchio PJ, Keese CR, Giaever I. Electrical method for detection of endothelial cell shape change in real time: Assessment of endothelial barrier function. Proc Natl Acad Sci U S A 89: 7919‐7923, 1992.
 272. Tiruppathi C, Song W, Bergenfeldt M, Sass P, Malik AB. Gp60 activation mediates albumin transcytosis in endothelial cells by tyrosine kinase‐dependent pathway. J Biol Chem 272: 25968‐25975, 1997.
 273. Tsukita S, Furuse M. The structure and function of claudins, cell adhesion molecules at tight junctions. Ann N Y Acad Sci 915: 129‐135, 2000.
 274. Tuder RM, Flook BE, Voelkel NF. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Invest 95: 1798‐1807, 1995.
 275. Tuma PL, Hubbard AL. Transcytosis: Crossing cellular barriers. Physiol Rev 83: 871‐932, 2003.
 276. Tzima E. Role of small GTPases in endothelial cytoskeletal dynamics and the shear stress response. Circ Res 98: 176‐185, 2006.
 277. Uhlig S, Heiny O. Measuring the weight of the isolated perfused rat lung during negative pressure ventilation. J Pharmacol Toxicol Methods 33: 147‐152, 1995.
 278. Uhlig S, von Bethmann AN. Determination of vascular compliance, interstitial compliance, and capillary filtration coefficient in rat isolated perfused lungs. J Pharmacol Toxicol Methods 37: 119‐127, 1997.
 279. Uhlig S, Wollin L, Wendel A. Contributions of thromboxane and leukotrienes to PAF‐induced impairment of lung function in the rat. J Appl Physiol 77: 262‐269, 1994.
 280. Vacca A, Iurlaro M, Ribatti D, Minischetti M, Nico B, Ria R, Pellegrino A, Dammacco F. Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood 94: 4143‐4155, 1999.
 281. van Hinsbergh VW, van Nieuw Amerongen GP. Endothelial hyperpermeability in vascular leakage. Vascul Pharmacol 39: 171‐172, 2002.
 282. van Nieuw Amerongen GP, Draijer R, Vermeer MA, van Hinsbergh VW. Transient and prolonged increase in endothelial permeability induced by histamine and thrombin: Role of protein kinases, calcium, and RhoA. Circ Res 83: 1115‐1123, 1998.
 283. Vandenbroucke E, Mehta D, Minshall R, Malik AB. Regulation of endothelial junctional permeability. Ann N Y Acad Sci 1123: 134‐145, 2008.
 284. Vasioukhin V, Fuchs E. Actin dynamics and cell‐cell adhesion in epithelia. Curr Opin Cell Biol 13: 76‐84, 2001.
 285. Verin AD, Birukova A, Wang P, Liu F, Becker P, Birukov K, Garcia JG. Microtubule disassembly increases endothelial cell barrier dysfunction: Role of MLC phosphorylation. Am J Physiol Lung Cell Mol Physiol 281: L565‐L574, 2001.
 286. Vestweber D. VE‐cadherin: The major endothelial adhesion molecule controlling cellular junctions and blood vessel formation. Arterioscler Thromb Vasc Biol 28: 223‐232, 2008.
 287. Vincent PA, Xiao K, Buckley KM, Kowalczyk AP. VE‐cadherin: Adhesion at arm's length. Am J Physiol Cell Physiol 286: C987‐C997, 2004.
 288. Vleminckx K, Kemler R. Cadherins and tissue formation: Integrating adhesion and signaling. Bioessays 21: 211‐220, 1999.
 289. Volberg T, Geiger B, Kartenbeck J, Franke WW. Changes in membrane‐microfilament interaction in intercellular adherens junctions upon removal of extracellular Ca2+ ions. J Cell Biol 102: 1832‐1842, 1986.
 290. Vouret‐Craviari V, Bourcier C, Boulter E, van Obberghen‐Schilling E. Distinct signals via Rho GTPases and Src drive shape changes by thrombin and sphingosine‐1‐phosphate in endothelial cells. J Cell Sci 115: 2475‐2484, 2002.
 291. Wade RH, Hyman AA. Microtubule structure and dynamics. Curr Opin Cell Biol 9: 12‐17, 1997.
 292. Wallez Y, Cand F, Cruzalegui F, Wernstedt C, Souchelnytskyi S, Vilgrain I, Huber P. Src kinase phosphorylates vascular endothelial‐cadherin in response to vascular endothelial growth factor: Identification of tyrosine 685 as the unique target site. Oncogene 26: 1067‐1077, 2007.
 293. Wallez Y, Huber P. Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis. Biochim Biophys Acta 1778: 794‐809, 2008.
 294. Waschke J, Burger S, Curry FR, Drenckhahn D, Adamson RH. Activation of Rac‐1 and Cdc42 stabilizes the microvascular endothelial barrier. Histochem Cell Biol 125: 397‐406, 2006.
 295. Waschke J, Curry FE, Adamson RH, Drenckhahn D. Regulation of actin dynamics is critical for endothelial barrier functions. Am J Physiol Heart Circ Physiol 288: H1296‐H1305, 2005.
 296. Waschke J, Drenckhahn D, Adamson RH, Barth H, Curry FE. cAMP protects endothelial barrier functions by preventing Rac‐1 inhibition. Am J Physiol Heart Circ Physiol 287: H2427‐H2433, 2004.
 297. Watabe‐Uchida M, Uchida N, Imamura Y, Nagafuchi A, Fujimoto K, Uemura T, Vermeulen S, van Roy F, Adamson ED, Takeichi M. alpha‐Catenin‐vinculin interaction functions to organize the apical junctional complex in epithelial cells. J Cell Biol 142: 847‐857, 1998.
 298. Weaver AM, Karginov AV, Kinley AW, Weed SA, Li Y, Parsons JT, Cooper JA. Cortactin promotes and stabilizes Arp2/3‐induced actin filament network formation. Curr Biol 11: 370‐374, 2001.
 299. Weaver AM, Young ME, Lee WL, Cooper JA. Integration of signals to the Arp2/3 complex. Curr Opin Cell Biol 15: 23‐30, 2003.
 300. Weed SA, Parsons JT. Cortactin: Coupling membrane dynamics to cortical actin assembly. Oncogene 20: 6418‐6434, 2001.
 301. Wegner A. Head to tail polymerization of actin. J Mol Biol 108: 139‐150, 1976.
 302. Weis S, Shintani S, Weber A, Kirchmair R, Wood M, Cravens A, McSharry H, Iwakura A, Yoon YS, Himes N, Burstein D, Doukas J, Soll R, Losordo D, Cheresh D. Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J Clin Invest 113: 885‐894, 2004.
 303. Weis SM, Cheresh DA. Pathophysiological consequences of VEGF‐induced vascular permeability. Nature 437: 497‐504, 2005.
 304. Winter MC, Shasby SS, Ries DR, Shasby DM. Histamine selectively interrupts VE‐cadherin adhesion independently of capacitive calcium entry. Am J Physiol Lung Cell Mol Physiol 287: L816‐L823, 2004.
 305. Witke W, Sharpe AH, Hartwig JH, Azuma T, Stossel TP, Kwiatkowski DJ. Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin. Cell 81: 41‐51, 1995.
 306. Wojciak‐Stothard B, Potempa S, Eichholtz T, Ridley AJ. Rho and Rac but not Cdc42 regulate endothelial cell permeability. J Cell Sci 114: 1343‐1355, 2001.
 307. Wojciak‐Stothard B, Ridley AJ. Rho GTPases and the regulation of endothelial permeability. Vascul Pharmacol 39: 187‐199, 2002.
 308. Wu HM, Yuan Y, Zawieja DC, Tinsley J, Granger HJ. Role of phospholipase C, protein kinase C, and calcium in VEGF‐induced venular hyperpermeability. Am J Physiol 276: H535‐H542, 1999.
 309. Wu MH, Guo M, Yuan SY, Granger HJ. Focal adhesion kinase mediates porcine venular hyperpermeability elicited by vascular endothelial growth factor. J Physiol 552: 691‐699, 2003.
 310. Wu MH, Ustinova E, Granger HJ. Integrin binding to fibronectin and vitronectin maintains the barrier function of isolated porcine coronary venules. J Physiol 532: 785‐791, 2001.
 311. Wu X, Suetsugu S, Cooper LA, Takenawa T, Guan JL. Focal adhesion kinase regulation of N‐WASP subcellular localization and function. J Biol Chem 279: 9565‐9576, 2004.
 312. Yanagisawa M, Kaverina IN, Wang A, Fujita Y, Reynolds AB, Anastasiadis PZ. A novel interaction between kinesin and p120 modulates p120 localization and function. J Biol Chem 279: 9512‐9521, 2004.
 313. Yin HL, Albrecht JH, Fattoum A. Identification of gelsolin, a Ca2+‐dependent regulatory protein of actin gel‐sol transformation, and its intracellular distribution in a variety of cells and tissues. J Cell Biol 91: 901‐906, 1981.
 314. Yin HL, Stossel TP. Control of cytoplasmic actin gel‐sol transformation by gelsolin, a calcium‐dependent regulatory protein. Nature 281: 583‐586, 1979.
 315. Zeng X, Wert SE, Federici R, Peters KG, Whitsett JA. VEGF enhances pulmonary vasculogenesis and disrupts lung morphogenesis in vivo. Dev Dyn 211: 215‐227, 1998.
 316. Zhao X, Peng X, Sun S, Park AY, Guan JL. Role of kinase‐independent and ‐dependent functions of FAK in endothelial cell survival and barrier function during embryonic development. J Cell Biol 189: 955‐965.
Further Reading
 1. Prasain N, Stevens T. The actin cytoskeleton in endothelial cell phenotypes. Microvasc Res 77: 53‐63, 2009.
 2. Romer LH, Birukov KG, Garcia JG. Focal adhesions: Paradigm for a signaling nexus. Circ Res 98: 606‐616, 2006.
 3. Wang L, Dudek SM. Regulation of vascular permeability by sphingosine 1‐phosphate Microvasc Res 77: 39‐45, 2009.
 4. Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE‐cadherin in the control of vascular permeability. J Cell Sci 121(Pt 13): 2115‐2122, 2008.
 5. Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability. Physiol Rev 86: 279‐367, 2006.
 6. Bazzoni G, Dejana E. Endothelial cell‐to‐cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84: 869‐901, 2004.
 7. Csortos C, Kolosova I, Verin AD. Regulation of vascular endothelial cell barrier function and cytoskeleton structure by protein phosphatases of the PPP family. Am J Physiol Lung Cell Mol Physiol 293: L843‐L854, 2007.
 8. Komarova YA, Mehta D, Malik AB. Dual regulation of endothelial junctional permeability. Sci STKE. 2007: re8, 2007.

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How to Cite

Stephen M. Vogel, Asrar B. Malik. Cytoskeletal Dynamics and Lung Fluid Balance. Compr Physiol 2012, 2: 449-478. doi: 10.1002/cphy.c100006