Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Endothelial Cell Regulation of Pulmonary Vascular Tone, Inflammation, and Coagulation

Neil M. Goldenberg, Wolfgang M. Kuebler

10.1002/cphy.c140024

Source: Volume 5, Issue 2, April 2015

Published online: March 2015

Full Article on Wiley Online Library



ABSTRACT

The pulmonary endothelium represents a heterogeneous cell monolayer covering the luminal surface of the entire lung vasculature. As such, this cell layer lies at a critical interface between the blood, airways, and lung parenchyma, and must act as a selective barrier between these diverse compartments. Lung endothelial cells are able to produce and secrete mediators, display surface receptor, and cellular adhesion molecules, and metabolize circulating hormones to influence vasomotor tone, both local and systemic inflammation, and coagulation functions. In this review, we will explore the role of the pulmonary endothelium in each of these systems, highlighting key regulatory functions of the pulmonary endothelial cell, as well as novel aspects of the pulmonary endothelium in contrast to the systemic cell type. The interactions between pulmonary endothelial cells and both leukocytes and platelets will be discussed in detail, and wherever possible, elements of endothelial control over physiological and pathophysiological processes will be examined. © 2015 American Physiological Society. Compr Physiol 5:531‐559, 2015.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Endothelial control of pulmonary vascular tone. An increase in intracellular Ca2+, either from internal stores or the extracellular fluid, triggers a series of intracellular signaling events that culminate in the binding of Ca2+ to calmodulin, activation of myosin light chain kinase (MLCK), and the phosphorylation of myosin. This, in turn, causes cell contraction and vasoconstriction. The most important regulator of this process in nitric oxide (NO). NO activates soluble guanylate cyclase (sGC), which produces cGMP. cGMP, acting via protein kinase G (PKG), can then inhibit various membrane channels to block the vasoconstrictive response. Additionally, PKG can inhibit sarcoplasmic reticulum (SR) Ca2+ channels, and can release myosin light chain phosphatase (MLCP) from inhibition by ROK, leading to dephosphorylation of MLC and the cessation of SMC contraction.
Figure 2. Figure 2. The pulmonary endothelial cell in inflammation. As highlighted in the text, the interaction between the pulmonary endothelium and circulating leukocytes differs greatly from that in the systemic circulation. Important physical factors exist which lead to leukocyte retention in the pulmonary capillary network. To traverse the lung vasculature, neutrophils must undergo cytoskeletal rearrangement so that they can fit through the small pulmonary vessels, which also have far lower flow rates than the systemic circulation. Because of this, the role of leukocyte rolling is diminished in the lung, and both CD18‐dependent and CD18‐independnet pathways exist for leukocyte extravasation.
Figure 3. Figure 3. The role of the pulmonary endothelium in platelet function. At rest, the pulmonary EC represents an antithrombogenic surface, repelling interactions with both platelets and clotting factors. This antiplatelet phenotype is largely due to constitutive secretion of PGI2 and NO by the resting lung EC. After endothelial injury, or inflammatory states of platelet and EC activation, the EC will secrete proplatelet aggregation factors, such as thromboxane A2. Activated platelets have increased availability of GPIIb/IIIa, which binds to elevated surface levels of ICAM‐1 and integrins. Furthermore, endothelial‐derived von Willebrand Factor (VWF) is released, and assists in cross‐linking platelets to form a mature platelet plug.
Figure 4. Figure 4. Regulation of nitric oxide production in the pulmonary endothelium. eNOS forms NO in the lung EC from L‐arginine, in the presence of the cofactor BH4, as a byproduct of L‐citrulline production. eNOS activity is enhanced by shear stress, intracellular Ca2+, and signaling by cytokines such as TGF‐β. Calcium enhances eNOS activity via direct binding of Ca2+/calmodulin (CaM) to eNOS, while phosphorylation of eNOS at Ser1177 by PI3‐Kinase and Akt also increases NO production. NO produced in this manner can freely diffuse into the PASMC, where it activates soluble guanylate cyclase to produce cGMP. cGMP then, via PKG function, produces PASMC relaxation. In the EC itself, NO inhibits neutrophil and platelet binding. On the other hand, reactive oxygen species (ROS), and conditions favoring uncoupling (including loss of BH4 availability and inflammatory states) decrease eNOS activity and NO production. Binding of eNOS to caveolin‐1 in caveolae downregulates is activity, as does tyrosine phosphorylation by PKC. Under such conditions, in addition to diminished NO production, uncoupled eNOS will produce superoxide, which then leads to further uncoupling in a positive feedback loop.
Figure 5. Figure 5. Arachidonic acid metabolism. The enzyme cytosolic phospholipase A2 (cPLA2), which is the dominant isoform in the pulmonary EC, liberates the 20 carbon fatty acid, arachidonic acid (AA) from plasma membrane phospholipids. Among several possible fates for AA, it can be metabolized by lipooxygenases (LOX) to produce Hydroperoxyeicosatetraenoic acid (HPETE), which can be further metabolized into leukotrienes. The activity of cyclooxygenase enzymes (COX) on AA produces prostaglandin H2 (PGH2) which can then be further processed into one of PGI2, PGE2, or thromboxane A2 (TxA2).
Figure 6. Figure 6. Pulmonary endothelial synthesis of vasoactive EET and HETE species. Further pathways of AA metabolism in the pulmonary endothelial cell can produce EET and HETE. The action of the cytochrome P450 epoxygenases 2C and 2J can produce a family of EET species, with various vasomotor and inflammatory functions, detailed in the text. The main catabolizer of EET species is the soluble epoxide hydrolase (sEH), which breaks EET species down into dihydroxyeicosatrienoic acids (DHET). Alternatively, ω or ω‐1 hydrolases can metabolize AA into 20‐ or 19‐HETE.
Figure 7. Figure 7. Pulmonary endothelial synthesis and secretion of ET‐1. ET‐1 is produced in the pulmonary endothelial cell in a prepro form, which is cleaved into pro‐ET‐1 (also called big ET‐1). The enzyme endothelin converting enzyme (ECE) then cleaves big ET‐1 into mature ET‐1, which then has both autocrine and paracrine functions within the lung vasculature. In the EC itself, ET‐1 can bind to the ETB receptor (ETBR), which results in nitric oxide (NO) and prostacyclin (PGI2) production. These two mediators can both subsequently act upon the smooth muscle cell to cause vasorelaxation. In a paracrine fashion, ET‐1 itself can bind to its receptors on smooth muscle cells, ETAR and ETBR, to cause G‐protein‐mediated activation of phospholipase C (PLC). The resultant production of inositol triphosphate (IP3) and diacylglycerol (DAG) results in SMC migration, and contraction, or proliferation, respectively.
Figure 8. Figure 8. Sources of reactive oxygen species in the pulmonary endothelial cell. A critically important source of ROS in the pulmonary EC is the family of NADPH oxidase (NOX) enzymes. Activated by angiotensin II, TGF‐β, and shear stress, NOX isoforms present in the lung can generate large quantities of ROS. Similarly, the mitochondrial electron transport chain can produce ROS, although controversy exists regarding whether hyperoxia or hypoxia favors this condition, and this controversy is discussed in the main text. Importantly, uncoupled eNOS produces ROS, and this ROS then leads to further eNOS uncoupling, which is an important propagator of inflammatory stress under a variety of pathological states. Elevated ROS levels leads to endothelial cytoskeletal changes, increased surface adhesion molecule expression, platelet adhesion, and a state referred to as endothelial dysfunction. Important enzymes such as superoxide dismutase exist to metabolize ROS and limit its accumulation.
Figure 9. Figure 9. Heterogeneous distribution of Weibel‐Pallade Bodies (WPB) in the lung endothelium. Representative electron micrographs of pulmonary endothelial cells from human lungs. WPB are indicated by arrowheads. Upper panels: High and low magnification images of extra‐alveolar endothelial cells, showing readily detectable WPB. Lower panels depict alveolar capillary endothelial cells, which are notably devoid of WPB. EC, endothelial cells, N, nucleus, BM, basement membrane, *, caveolae. Reproduced, with permission, from (266).
Figure 10. Figure 10. Transcytosis of interleukin‐8 by endothelial cells. Stacked and reconstructed electron micrographs of human skin venular endothelial cells, with gold labeling of interleukin‐8 (IL‐8). (A) IL‐8 binding and uptake at the basolateral (abluminal) surface of the venular EC. (B) and (C) demonstrate IL‐8 in vesicles below the plasma membrane. (D) and (E) demonstrate IL‐8 now subsequently appearing at the luminal surface of the EC. (F) Colocalization of IL‐8 (10 nm gold) and caveolin‐1 (5 nm gold). Reproduced, with permission, from (148).
Figure 11. Figure 11. Structure of the endothelial glycocalyx and endothelial surface layer (ESL). At the luminal surface of the pulmonary EC, the glycocalyx comprises a thin layer of plasma membrane glycoproteins and glycolipids. External to that is a thicker layer of glycosaminoglycans (GAG), heparan sulfate, hyaluronan, and other molecules, termed the ESL. These layers (A) separate the EC surface from the circulating plasma, (B) allow for mechanosensation and outside‐in signaling to the EC, (C) performs a critical role in maintaining the endothelial barrier, and (D) can be importantly degraded and modified during periods of inflammation.
Figure 12. Figure 12. The endothelial glycocalyx in vivo, and its degradation by LPS. (A) Schematic representation of the glycocalyx and endothelial surface layer (ESL). Note that the glycocalyx is not permeable to large molecules such as fluorescent dextrans. Therefore, measurement of vessel diameter by visible light microscopy versus fluorescence should allow for the measurement of the ESL. The images in the right of the panel show mouse sub‐pleural microvessels (MV) imaged with visible light (DIC) or fluorescence (FITC). The difference between the DIC and FITC width represents the ESL. (A) Alveolus. (B) Group data of calculated ESL thickness as in (A), taken from mice treated with LPS or TNF‐α, demonstrating how inflammatory stimuli can degrade the ESL. (C) These effects are not seen in mice lacking functional TNF receptors. Reproduced, with permission, from (197).
Figure 13. Figure 13. Pulmonary endothelial angiotensin signaling. The majority of conversion of AngI to AngII is carried out by angiotensin converting enzyme (ACE), bound to the EC surface. AngII can then bind to AT1R or AT2R (left side). Signaling through AT1R results in G‐protein‐mediated release of IP3 and DAG, as well as stimulation of MAP kinases. The downstream effects include PASMC contraction and migration, as well as EC ROS production and vascular remodeling. Signaling via the AT2R is incompletely understood in the lung, but in general antagonizes the effects of AT1R signaling, leading to PASMC relaxation, and protection from adverse remodeling. The cell on the right depicts further metabolism of AngII by ACE2, producing Ang(1‐7), which subsequently binds the Mas receptor. Mas has a highly protective effect during states of acute lung injury and inflammation, decreasing ROS production, enhancing NO release, and protecting against thrombosis and EC apoptosis.
Figure 14. Figure 14. The conducted response in hypoxic pulmonary vasoconstriction. (A) Intravital microscopic images taken from wild‐type (top panels) or Cx40−/− mice (bottom panels) during normoxic or hypoxic ventilation, as indicated. Endothelial cells have been loaded with the voltage‐sensitive fluorophore, di‐8‐ANEPPS. Arteriolar vessel margins are indicated by dotted lines. Capillary endothelial cells are circled, while arteriolar EC are indicated by squares. Not that in wild‐type mice, depolarization in response to hypoxia occurs in both the capillary and arteriolar EC. However, in Cx40−/− mice, only the capillary EC depolarize, indicating the requirement of gap junction communication for the conducted response. (C) and (D) show group data describing the above. In (D), depolarization in response to hypoxia is not seen in the pulmonary arteriolar EC in Cx40−/− mice, indicative of the requirement for gap junctional communication. Reproduced, with permission, from (241).
Figure 15. Figure 15. Schematic diagram representing the conducted response. It is hypothesized that hypoxia inhibits oxygen‐sensitive K+ channels, leading to EC depolarization at the alveolar capillary level. This depolarization spreads between EC in a retrograde fashion to the muscularized arteriolar EC via Cx40‐containing gap junctions. At this point, communication with the PASMC can occur, resulting in vasoconstriction. A contribution of myoendothelial gap junctions containing Cx43 and Cx40 is likely involved in this process.


Figure 1. Endothelial control of pulmonary vascular tone. An increase in intracellular Ca2+, either from internal stores or the extracellular fluid, triggers a series of intracellular signaling events that culminate in the binding of Ca2+ to calmodulin, activation of myosin light chain kinase (MLCK), and the phosphorylation of myosin. This, in turn, causes cell contraction and vasoconstriction. The most important regulator of this process in nitric oxide (NO). NO activates soluble guanylate cyclase (sGC), which produces cGMP. cGMP, acting via protein kinase G (PKG), can then inhibit various membrane channels to block the vasoconstrictive response. Additionally, PKG can inhibit sarcoplasmic reticulum (SR) Ca2+ channels, and can release myosin light chain phosphatase (MLCP) from inhibition by ROK, leading to dephosphorylation of MLC and the cessation of SMC contraction.


Figure 2. The pulmonary endothelial cell in inflammation. As highlighted in the text, the interaction between the pulmonary endothelium and circulating leukocytes differs greatly from that in the systemic circulation. Important physical factors exist which lead to leukocyte retention in the pulmonary capillary network. To traverse the lung vasculature, neutrophils must undergo cytoskeletal rearrangement so that they can fit through the small pulmonary vessels, which also have far lower flow rates than the systemic circulation. Because of this, the role of leukocyte rolling is diminished in the lung, and both CD18‐dependent and CD18‐independnet pathways exist for leukocyte extravasation.


Figure 3. The role of the pulmonary endothelium in platelet function. At rest, the pulmonary EC represents an antithrombogenic surface, repelling interactions with both platelets and clotting factors. This antiplatelet phenotype is largely due to constitutive secretion of PGI2 and NO by the resting lung EC. After endothelial injury, or inflammatory states of platelet and EC activation, the EC will secrete proplatelet aggregation factors, such as thromboxane A2. Activated platelets have increased availability of GPIIb/IIIa, which binds to elevated surface levels of ICAM‐1 and integrins. Furthermore, endothelial‐derived von Willebrand Factor (VWF) is released, and assists in cross‐linking platelets to form a mature platelet plug.


Figure 4. Regulation of nitric oxide production in the pulmonary endothelium. eNOS forms NO in the lung EC from L‐arginine, in the presence of the cofactor BH4, as a byproduct of L‐citrulline production. eNOS activity is enhanced by shear stress, intracellular Ca2+, and signaling by cytokines such as TGF‐β. Calcium enhances eNOS activity via direct binding of Ca2+/calmodulin (CaM) to eNOS, while phosphorylation of eNOS at Ser1177 by PI3‐Kinase and Akt also increases NO production. NO produced in this manner can freely diffuse into the PASMC, where it activates soluble guanylate cyclase to produce cGMP. cGMP then, via PKG function, produces PASMC relaxation. In the EC itself, NO inhibits neutrophil and platelet binding. On the other hand, reactive oxygen species (ROS), and conditions favoring uncoupling (including loss of BH4 availability and inflammatory states) decrease eNOS activity and NO production. Binding of eNOS to caveolin‐1 in caveolae downregulates is activity, as does tyrosine phosphorylation by PKC. Under such conditions, in addition to diminished NO production, uncoupled eNOS will produce superoxide, which then leads to further uncoupling in a positive feedback loop.


Figure 5. Arachidonic acid metabolism. The enzyme cytosolic phospholipase A2 (cPLA2), which is the dominant isoform in the pulmonary EC, liberates the 20 carbon fatty acid, arachidonic acid (AA) from plasma membrane phospholipids. Among several possible fates for AA, it can be metabolized by lipooxygenases (LOX) to produce Hydroperoxyeicosatetraenoic acid (HPETE), which can be further metabolized into leukotrienes. The activity of cyclooxygenase enzymes (COX) on AA produces prostaglandin H2 (PGH2) which can then be further processed into one of PGI2, PGE2, or thromboxane A2 (TxA2).


Figure 6. Pulmonary endothelial synthesis of vasoactive EET and HETE species. Further pathways of AA metabolism in the pulmonary endothelial cell can produce EET and HETE. The action of the cytochrome P450 epoxygenases 2C and 2J can produce a family of EET species, with various vasomotor and inflammatory functions, detailed in the text. The main catabolizer of EET species is the soluble epoxide hydrolase (sEH), which breaks EET species down into dihydroxyeicosatrienoic acids (DHET). Alternatively, ω or ω‐1 hydrolases can metabolize AA into 20‐ or 19‐HETE.


Figure 7. Pulmonary endothelial synthesis and secretion of ET‐1. ET‐1 is produced in the pulmonary endothelial cell in a prepro form, which is cleaved into pro‐ET‐1 (also called big ET‐1). The enzyme endothelin converting enzyme (ECE) then cleaves big ET‐1 into mature ET‐1, which then has both autocrine and paracrine functions within the lung vasculature. In the EC itself, ET‐1 can bind to the ETB receptor (ETBR), which results in nitric oxide (NO) and prostacyclin (PGI2) production. These two mediators can both subsequently act upon the smooth muscle cell to cause vasorelaxation. In a paracrine fashion, ET‐1 itself can bind to its receptors on smooth muscle cells, ETAR and ETBR, to cause G‐protein‐mediated activation of phospholipase C (PLC). The resultant production of inositol triphosphate (IP3) and diacylglycerol (DAG) results in SMC migration, and contraction, or proliferation, respectively.


Figure 8. Sources of reactive oxygen species in the pulmonary endothelial cell. A critically important source of ROS in the pulmonary EC is the family of NADPH oxidase (NOX) enzymes. Activated by angiotensin II, TGF‐β, and shear stress, NOX isoforms present in the lung can generate large quantities of ROS. Similarly, the mitochondrial electron transport chain can produce ROS, although controversy exists regarding whether hyperoxia or hypoxia favors this condition, and this controversy is discussed in the main text. Importantly, uncoupled eNOS produces ROS, and this ROS then leads to further eNOS uncoupling, which is an important propagator of inflammatory stress under a variety of pathological states. Elevated ROS levels leads to endothelial cytoskeletal changes, increased surface adhesion molecule expression, platelet adhesion, and a state referred to as endothelial dysfunction. Important enzymes such as superoxide dismutase exist to metabolize ROS and limit its accumulation.


Figure 9. Heterogeneous distribution of Weibel‐Pallade Bodies (WPB) in the lung endothelium. Representative electron micrographs of pulmonary endothelial cells from human lungs. WPB are indicated by arrowheads. Upper panels: High and low magnification images of extra‐alveolar endothelial cells, showing readily detectable WPB. Lower panels depict alveolar capillary endothelial cells, which are notably devoid of WPB. EC, endothelial cells, N, nucleus, BM, basement membrane, *, caveolae. Reproduced, with permission, from (266).


Figure 10. Transcytosis of interleukin‐8 by endothelial cells. Stacked and reconstructed electron micrographs of human skin venular endothelial cells, with gold labeling of interleukin‐8 (IL‐8). (A) IL‐8 binding and uptake at the basolateral (abluminal) surface of the venular EC. (B) and (C) demonstrate IL‐8 in vesicles below the plasma membrane. (D) and (E) demonstrate IL‐8 now subsequently appearing at the luminal surface of the EC. (F) Colocalization of IL‐8 (10 nm gold) and caveolin‐1 (5 nm gold). Reproduced, with permission, from (148).


Figure 11. Structure of the endothelial glycocalyx and endothelial surface layer (ESL). At the luminal surface of the pulmonary EC, the glycocalyx comprises a thin layer of plasma membrane glycoproteins and glycolipids. External to that is a thicker layer of glycosaminoglycans (GAG), heparan sulfate, hyaluronan, and other molecules, termed the ESL. These layers (A) separate the EC surface from the circulating plasma, (B) allow for mechanosensation and outside‐in signaling to the EC, (C) performs a critical role in maintaining the endothelial barrier, and (D) can be importantly degraded and modified during periods of inflammation.


Figure 12. The endothelial glycocalyx in vivo, and its degradation by LPS. (A) Schematic representation of the glycocalyx and endothelial surface layer (ESL). Note that the glycocalyx is not permeable to large molecules such as fluorescent dextrans. Therefore, measurement of vessel diameter by visible light microscopy versus fluorescence should allow for the measurement of the ESL. The images in the right of the panel show mouse sub‐pleural microvessels (MV) imaged with visible light (DIC) or fluorescence (FITC). The difference between the DIC and FITC width represents the ESL. (A) Alveolus. (B) Group data of calculated ESL thickness as in (A), taken from mice treated with LPS or TNF‐α, demonstrating how inflammatory stimuli can degrade the ESL. (C) These effects are not seen in mice lacking functional TNF receptors. Reproduced, with permission, from (197).


Figure 13. Pulmonary endothelial angiotensin signaling. The majority of conversion of AngI to AngII is carried out by angiotensin converting enzyme (ACE), bound to the EC surface. AngII can then bind to AT1R or AT2R (left side). Signaling through AT1R results in G‐protein‐mediated release of IP3 and DAG, as well as stimulation of MAP kinases. The downstream effects include PASMC contraction and migration, as well as EC ROS production and vascular remodeling. Signaling via the AT2R is incompletely understood in the lung, but in general antagonizes the effects of AT1R signaling, leading to PASMC relaxation, and protection from adverse remodeling. The cell on the right depicts further metabolism of AngII by ACE2, producing Ang(1‐7), which subsequently binds the Mas receptor. Mas has a highly protective effect during states of acute lung injury and inflammation, decreasing ROS production, enhancing NO release, and protecting against thrombosis and EC apoptosis.


Figure 14. The conducted response in hypoxic pulmonary vasoconstriction. (A) Intravital microscopic images taken from wild‐type (top panels) or Cx40−/− mice (bottom panels) during normoxic or hypoxic ventilation, as indicated. Endothelial cells have been loaded with the voltage‐sensitive fluorophore, di‐8‐ANEPPS. Arteriolar vessel margins are indicated by dotted lines. Capillary endothelial cells are circled, while arteriolar EC are indicated by squares. Not that in wild‐type mice, depolarization in response to hypoxia occurs in both the capillary and arteriolar EC. However, in Cx40−/− mice, only the capillary EC depolarize, indicating the requirement of gap junction communication for the conducted response. (C) and (D) show group data describing the above. In (D), depolarization in response to hypoxia is not seen in the pulmonary arteriolar EC in Cx40−/− mice, indicative of the requirement for gap junctional communication. Reproduced, with permission, from (241).


Figure 15. Schematic diagram representing the conducted response. It is hypothesized that hypoxia inhibits oxygen‐sensitive K+ channels, leading to EC depolarization at the alveolar capillary level. This depolarization spreads between EC in a retrograde fashion to the muscularized arteriolar EC via Cx40‐containing gap junctions. At this point, communication with the PASMC can occur, resulting in vasoconstriction. A contribution of myoendothelial gap junctions containing Cx43 and Cx40 is likely involved in this process.
References
 1. Adamson RH . Permeability of frog mesenteric capillaries after partial pronase digestion of the endothelial glycocalyx. J Physiol (Lond) 428: 1‐13, 1990.
 2. Adhikari NKJ , Burns KEA , Friedrich JO , Granton JT , Cook DJ , Meade MO . Effect of nitric oxide on oxygenation and mortality in acute lung injury: Systematic review and meta‐analysis. BMJ 334: 779‐779, 2007.
 3. Afshari A , Brok J , Møller AM , Wetterslev J . Inhaled nitric oxide for acute respiratory distress syndrome and acute lung injury in adults and children: A systematic review with meta‐analysis and trial sequential analysis. Anesth Analg 112: 1411‐1421, 2011.
 4. Aird WC . Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 100: 158‐173, 2007a.
 5. Aird WC . Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res 100: 174‐190, 2007b.
 6. Angiolillo DJ , Ferreiro JL . Antiplatelet and anticoagulant therapy for atherothrombotic disease: The role of current and emerging agents. Am J Cardiovasc Drugs 13: 233‐250, 2013.
 7. Archer SL . Riociguat for pulmonary hypertension–a glass half full. N Engl J Med 369: 386‐388, 2013.
 8. Archer SL , Reeve HL , Michelakis E , Puttagunta L , Waite R , Nelson DP , Dinauer MC , Weir EK . O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase. Proc Natl Acad Sci U S A 96: 7944‐7949, 1999.
 9. Aszódi A , Pfeifer A , Ahmad M , Glauner M , Zhou XH , Ny L , Andersson KE , Kehrel B , Offermanns S , Fässler R . The vasodilator‐stimulated phosphoprotein (VASP) is involved in cGMP‐ and cAMP‐mediated inhibition of agonist‐induced platelet aggregation, but is dispensable for smooth muscle function. EMBO J 18: 37‐48, 1999.
 10. Barrington KJ , Finer N . Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev: CD000509, 2010.
 11. Barst RJ , Rubin LJ , Long WA , McGoon MD , Rich S , Badesch DB , Groves BM , Tapson VF , Bourge RC , Brundage BH , Koerner SK , Langleben D , Keller CA , Murali S , Uretsky BF , Clayton LM , Jöbsis MM , Blackburn SD , Shortino D , Crow JW , Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334: 296‐301, 1996.
 12. Basora N , Boulay G , Bilodeau L , Rousseau E , Payet MD . 20‐hydroxyeicosatetraenoic acid (20‐HETE) activates mouse TRPC6 channels expressed in HEK293 cells. J Biol Chem 278: 31709‐31716, 2003.
 13. Bäck M , Walch L , Norel X , Gascard JP , Mazmanian G , Brink C . Modulation of vascular tone and reactivity by nitric oxide in porcine pulmonary arteries and veins. Acta Physiol Scand 174: 9‐15, 2002.
 14. Beck‐Schimmer B , Schimmer RC , Warner RL , Schmal H , Nordblom G , Flory CM , Lesch ME , Friedl HP , Schrier DJ , Ward PA . Expression of lung vascular and airway ICAM‐1 after exposure to bacterial lipopolysaccharide. Am J Respir Cell Mol Biol 17: 344‐352, 1997.
 15. Beckman JS , Beckman TW , Chen J , Marshall PA , Freeman BA . Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 87: 1620‐1624, 1990.
 16. Bernardo A , Ball C , Nolasco L , Choi H , Moake JL , Dong JF . Platelets adhered to endothelial cell‐bound ultra‐large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress. J Thromb Haemost 3: 562‐570, 2005.
 17. Bina S , Hart JL , Sei Y , Muldoon SM . Factors contributing to differences in the regulation of cGMP in isolated porcine pulmonary vessels. Eur J Pharmacol 351: 253‐260, 1998.
 18. Birks EK , Bousamra M , Presberg K , Marsh JA , Effros RM , Jacobs ER . Human pulmonary arteries dilate to 20‐HETE, an endogenous eicosanoid of lung tissue. Am J Physiol 272: L823‐L829, 1997.
 19. Birukova AA , Tian X , Cokic I , Beckham Y , Gardel ML , Birukov KG . Endothelial barrier disruption and recovery is controlled by substrate stiffness. Microvasc Res 87: 50‐57, 2013.
 20. Bodiga S , Gruenloh SK , Gao Y , Manthati VL , Dubasi N , Falck JR , Medhora M , Jacobs ER . 20‐HETE‐induced nitric oxide production in pulmonary artery endothelial cells is mediated by NADPH oxidase, H2O2, and PI3‐kinase/Akt. Am J Physiol Lung Cell Mol Physiol 298: L564‐L574, 2010.
 21. Boulanger C , Lüscher TF . Release of endothelin from the porcine aorta. Inhibition by endothelium‐derived nitric oxide. J Clin Invest 85: 587‐590, 1990.
 22. Brasier AR , Recinos A , Eledrisi MS . Vascular inflammation and the renin‐angiotensin system. Arterioscler Thromb Vasc Biol 22: 1257‐1266, 2002.
 23. Brueckl C , Kaestle S , Kerem A , Habazettl H , Krombach F , Kuppe H , Kuebler WM . Hyperoxia‐induced reactive oxygen species formation in pulmonary capillary endothelial cells in situ. Am J Respir Cell Mol Biol 34: 453‐463, 2006.
 24. Bucci M , Roviezzo F , Posadas I , Yu J , Parente L , Sessa WC , Ignarro LJ , Cirino G . Endothelial nitric oxide synthase activation is critical for vascular leakage during acute inflammation in vivo. Proc Natl Acad Sci USA 102: 904‐908, 2005.
 25. Budhiraja R , Tuder RM , Hassoun PM . Endothelial dysfunction in pulmonary hypertension. Circulation 109: 159‐165, 2004.
 26. Bueltmann M , Kong X , Mertens M , Yin N , Yin J , Liu Z , Koster A , Kuppe H , Kuebler WM . Inhaled milrinone attenuates experimental acute lung injury. Intensive Care Med 35: 171‐178, 2009.
 27. Camacho M , Rodríguez C , Guadall A , Alcolea S , Orriols M , Escudero J‐R , Martínez‐González J , Vila L . Hypoxia upregulates PGI‐synthase and increases PGI2 release in human vascular cells exposed to inflammatory stimuli. J Lipid Res 52: 720‐731, 2011.
 28. Carey RM , Jin XH , Siragy HM . Role of the angiotensin AT2 receptor in blood pressure regulation and therapeutic implications. Am J Hypertens 14: 98S‐102S, 2001.
 29. Channick RN , Simonneau G , Sitbon O , Robbins IM , Frost A , Tapson VF , Badesch DB , Roux S , Rainisio M , Bodin F , Rubin LJ . Effects of the dual endothelin‐receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo‐controlled study. Lancet 358: 1119‐1123, 2001.
 30. Christman BW . Lipid mediator dysregulation in primary pulmonary hypertension. Chest 114: 205S‐207S, 1998.
 31. Clarenbach CF , Senn O , Sievi NA , Camen G , van Gestel AJR , Rossi VA , Puhan MA , Thurnheer R , Russi EW , Kohler M . Determinants of endothelial function in patients with COPD. Eur Respir J 42: 1194‐1204, 2013.
 32. Clayton JA , Collins FS . Policy: NIH to balance sex in cell and animal studies. Nature 509: 282‐283, 2014.
 33. Cohen RA , Weisbrod RM , Gericke M , Yaghoubi M , Bierl C , Bolotina VM . Mechanism of nitric oxide‐induced vasodilatation: Refilling of intracellular stores by sarcoplasmic reticulum Ca2 +ATPase and inhibition of store‐operated Ca2+ influx. Circ Res 84: 210‐219, 1999.
 34. Coleman RA , Smith WL , Narumiya S . International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev 46: 205‐229, 1994.
 35. Collins SR , Blank RS , Deatherage LS , Dull RO . Special article: The endothelial glycocalyx: Emerging concepts in pulmonary edema and acute lung injury. Anesth Analg 117: 664‐674, 2013.
 36. Costanzo A , Moretti F , Burgio VL , Bravi C , Guido F , Levrero M , Puri PL . Endothelial activation by angiotensin II through NFkappaB and p38 pathways: Involvement of NFkappaB‐inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin. J Cell Physiol 195: 402‐410, 2003.
 37. Crapo JD , Barry BE , Gehr P , Bachofen M , Weibel ER . Cell number and cell characteristics of the normal human lung. Am Rev Respir Dis 125: 740‐745, 1982.
 38. Dai H‐L , Guo Y , Guang X‐F , Xiao Z‐C , Zhang M , Yin X‐L . The changes of serum angiotensin‐converting enzyme 2 in patients with pulmonary arterial hypertension due to congenital heart disease. Cardiology 124: 208‐212, 2013.
 39. Damico R , Zulueta JJ , Hassoun PM . Pulmonary endothelial cell NOX. Am J Respir Cell Mol Biol 47: 129‐139, 2012.
 40. Davis ME , Grumbach IM , Fukai T , Cutchins A , Harrison DG . Shear stress regulates endothelial nitric‐oxide synthase promoter activity through nuclear factor kappaB binding. J Biol Chem 279: 163‐168, 2004.
 41. Davì G , Patrono C . Platelet activation and atherothrombosis. N Engl J Med 357: 2482‐2494, 2007.
 42. Dayal S , Wilson KM , Motto DG , Miller FJ , Chauhan AK , Lentz SR . Hydrogen peroxide promotes aging‐related platelet hyperactivation and thrombosis. Circulation 127: 1308‐1316, 2013.
 43. De Caterina R , Libby P , Peng HB , Thannickal VJ , Rajavashisth TB , Gimbrone MA , Shin WS , Liao JK . Nitric oxide decreases cytokine‐induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96: 60‐68, 1995.
 44. de Wit C , Roos F , Bolz SS , Kirchhoff S , Krüger O , Willecke K , Pohl U . Impaired conduction of vasodilation along arterioles in connexin40‐deficient mice. Circ Res 86: 649‐655, 2000.
 45. Dempsie Y , MacLean MR . The influence of gender on the development of pulmonary arterial hypertension. Exp Physiol 98: 1257‐1261, 2013.
 46. Deng Y , Edin ML , Theken KN , Schuck RN , Flake GP , Kannon MA , DeGraff LM , Lih FB , Foley J , Bradbury JA , Graves JP , Tomer KB , Falck JR , Zeldin DC , Lee CR . Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice. FASEB J 25: 703‐713, 2011.
 47. Denis CV , André P , Saffaripour S , Wagner DD . Defect in regulated secretion of P‐selectin affects leukocyte recruitment in von Willebrand factor‐deficient mice. Proc Natl Acad Sci U S A 98: 4072‐4077, 2001.
 48. Desireddi JR , Farrow KN , Marks JD , Waypa GB , Schumacker PT . Hypoxia increases ROS signaling and cytosolic Ca(2+) in pulmonary artery smooth muscle cells of mouse lungs slices. Antioxid Redox Signal 12: 595‐602, 2010.
 49. Dimmeler S , Zeiher AM . Reactive oxygen species and vascular cell apoptosis in response to angiotensin II and pro‐atherosclerotic factors. Regul Pept 90: 19‐25, 2000.
 50. Doerschuk CM . Mechanisms of leukocyte sequestration in inflamed lungs. Microcirculation 8: 71‐88, 2001.
 51. Doerschuk CM , Mizgerd JP , Kubo H , Qin L , Kumasaka T . Adhesion molecules and cellular biomechanical changes in acute lung injury: Giles F. Filley Lecture. Chest 116: 37S‐43S, 1999.
 52. Dupuis J , Hoeper MM . Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J 31: 407‐415, 2008.
 53. Edwards JC , Ignarro LJ , Hyman AL , Kadowitz PJ . Relaxation of intrapulmonary artery and vein by nitrogen oxide‐containing vasodilators and cyclic GMP. J Pharmacol Exp Ther 228: 33‐42, 1984.
 54. Eto M , Senba S , Morita F , Yazawa M . Molecular cloning of a novel phosphorylation‐dependent inhibitory protein of protein phosphatase‐1 (CPI17) in smooth muscle: Its specific localization in smooth muscle. FEBS Lett 410: 356‐360, 1997.
 55. Fagan KA , Tyler RC , Sato K , Fouty BW , Morris KG , Huang PL , McMurtry IF , Rodman DM . Relative contributions of endothelial, inducible, and neuronal NOS to tone in the murine pulmonary circulation. Am J Physiol 277: L472‐L478, 1999.
 56. Farkas L , Farkas D , Ask K , Möller A , Gauldie J , Margetts P , Inman M , Kolb M . VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J Clin Invest 119: 1298‐1311, 2009.
 57. Feldmer M , Kaling M , Takahashi S , Mullins JJ , Ganten D . Glucocorticoid‐ and estrogen‐responsive elements in the 5'‐flanking region of the rat angiotensinogen gene. J Hypertens 9: 1005‐1012, 1991.
 58. Fellner SK , Arendshorst WJ . Complex interactions of NO/cGMP/PKG systems on Ca2+ signaling in afferent arteriolar vascular smooth muscle. Am J Physiol Heart Circ Physiol 298: H144‐H151, 2010.
 59. Feng J , Ito M , Ichikawa K , Isaka N , Nishikawa M , Hartshorne DJ , Nakano T . Inhibitory phosphorylation site for Rho‐associated kinase on smooth muscle myosin phosphatase. J Biol Chem 274: 37385‐37390, 1999.
 60. Feron O , Saldana F , Michel JB , Michel T . The endothelial nitric‐oxide synthase‐caveolin regulatory cycle. J Biol Chem 273: 3125‐3128, 1998.
 61. Ferrario CM , Brosnihan KB , Diz DI , Jaiswal N , Khosla MC , Milsted A , Tallant EA . Angiotensin‐(1‐7): a new hormone of the angiotensin system. Hypertension 18: III126‐III133, 1991.
 62. Ferrario CM , Chappell MC , Dean RH , Iyer SN . Novel angiotensin peptides regulate blood pressure, endothelial function, and natriuresis. J Am Soc Nephrol 9: 1716‐1722, 1998.
 63. Ferroni P , Vazzana N , Riondino S , Cuccurullo C , Guadagni F , Davì G . Platelet function in health and disease: From molecular mechanisms, redox considerations to novel therapeutic opportunities. Antioxid Redox Signal 17: 1447‐1485, 2012.
 64. Figueroa XF , Duling BR . Gap junctions in the control of vascular function. Antioxid Redox Signal 11: 251‐266, 2009.
 65. Fischer M , Baessler A , Schunkert H . Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc Res 53: 672‐677, 2002.
 66. Fitzpatrick FA , Ennis MD , Baze ME , Wynalda MA , McGee JE , Liggett WF . Inhibition of cyclooxygenase activity and platelet aggregation by epoxyeicosatrienoic acids. Influence of stereochemistry. J Biol Chem 261: 15334‐15338, 1986.
 67. Fleming I . DiscrEET regulators of homeostasis: Epoxyeicosatrienoic acids, cytochrome P450 epoxygenases and vascular inflammation. Trends Pharmacol Sci 28: 448‐452, 2007.
 68. Fleming I , Rueben A , Popp R , Fisslthaler B , Schrodt S , Sander A , Haendeler J , Falck JR , Morisseau C , Hammock BD , Busse R . Epoxyeicosatrienoic acids regulate Trp channel dependent Ca2+ signaling and hyperpolarization in endothelial cells. Arterioscler Thromb Vasc Biol 27: 2612‐2618, 2007.
 69. Foudi N , Kotelevets L , Louedec L , Leséche G , Henin D , Chastre E , Norel X . Vasorelaxation induced by prostaglandin E2 in human pulmonary vein: Role of the EP4 receptor subtype. Br J Pharmacol 154: 1631‐1639, 2008.
 70. Förstermann U , Münzel T . Endothelial nitric oxide synthase in vascular disease: From marvel to menace. Circulation 113: 1708‐1714, 2006.
 71. Fraga‐Silva RA , Pinheiro SVB , Gonçalves ACC , Alenina N , Bader M , Santos RAS . The antithrombotic effect of angiotensin‐(1‐7) involves mas‐mediated NO release from platelets. Mol Med 14: 28‐35, 2008.
 72. Frenette PS , Johnson RC , Hynes RO , Wagner DD . Platelets roll on stimulated endothelium in vivo: An interaction mediated by endothelial P‐selectin. Proc Natl Acad Sci U S A 92: 7450‐7454, 1995.
 73. Fritts HW , Harris P , Clauss RH , Odell JE , Cournand A . The effect of acetylcholine on the human pulmonary circulation under normal and hypoxic conditions. J Clin Invest 37: 99‐110, 1958.
 74. Fuchs A , Weibel ER . [Morphometric study of the distribution of a specific cytoplasmatic organoid in the rat's endothelial cells]. Z Zellforsch Mikrosk Anat 73: 1‐9, 1966.
 75. Furchgott RF , Zawadzki JV . The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373‐376, 1980.
 76. Galiè N , Ghofrani HA , Torbicki A , Barst RJ , Rubin LJ , Badesch D , Fleming T , Parpia T , Burgess G , Branzi A , Grimminger F , Kurzyna M , Simonneau G , Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353: 2148‐2157, 2005.
 77. Galiè N , Olschewski H , Oudiz RJ , Torres F , Frost A , Ghofrani HA , Badesch DB , McGoon MD , McLaughlin VV , Roecker EB , Gerber MJ , Dufton C , Wiens BL , Rubin LJ , Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double‐Blind, Placebo‐Controlled, Multicenter, Efficacy Studies (ARIES) Group. Ambrisentan for the treatment of pulmonary arterial hypertension: Results of the ambrisentan in pulmonary arterial hypertension, randomized, double‐blind, placebo‐controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 117: 3010‐3019, 2008.
 78. Gao Y , Raj JU . Role of veins in regulation of pulmonary circulation. Am J Physiol Lung Cell Mol Physiol 288: L213‐L226, 2005.
 79. Geiger M , Stone A , Mason SN , Oldham KT , Guice KS . Differential nitric oxide production by microvascular and macrovascular endothelial cells. Am J Physiol 273: L275‐L281, 1997.
 80. Ghofrani H‐A , D'Armini AM , Grimminger F , Hoeper MM , Jansa P , Kim NH , Mayer E , Simonneau G , Wilkins MR , Fritsch A , Neuser D , Weimann G , Wang C , CHEST‐1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 369: 319‐329, 2013.
 81. Ghofrani H‐A , Galiè N , Grimminger F , Grünig E , Humbert M , Jing Z‐C , Keogh AM , Langleben D , Kilama MO , Fritsch A , Neuser D , Rubin LJ , PATENT‐1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369: 330‐340, 2013.
 82. Giles TD , Sander GE , Nossaman BD , Kadowitz PJ . Impaired vasodilation in the pathogenesis of hypertension: Focus on nitric oxide, endothelial‐derived hyperpolarizing factors, and prostaglandins. J Clin Hypertens (Greenwich) 14: 198‐205, 2012.
 83. Goger B , Halden Y , Rek A , Mösl R , Pye D , Gallagher J , Kungl AJ . Different affinities of glycosaminoglycan oligosaccharides for monomeric and dimeric interleukin‐8: A model for chemokine regulation at inflammatory sites. Biochemistry 41: 1640‐1646, 2002.
 84. Goodenough DA , Paul DL . Beyond the gap: Functions of unpaired connexon channels. Nat Rev Mol Cell Biol 4: 285‐294, 2003.
 85. Govers R , Rabelink TJ . Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol 280: F193‐F206, 2001.
 86. Griffiths MJD , Evans TW . Inhaled nitric oxide therapy in adults. N Engl J Med 353: 2683‐2695, 2005.
 87. Hagiwara S , Iwasaka H , Matumoto S , Hidaka S , Noguchi T . Effects of an angiotensin‐converting enzyme inhibitor on the inflammatory response in in vivo and in vitro models. Crit Care Med 37: 626‐633, 2009.
 88. Hahn C , Schwartz MA . Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10: 53‐62, 2009.
 89. Halder G , Dupont S , Piccolo S . Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat Rev Mol Cell Biol 13: 591‐600, 2012.
 90. Hampl V , Herget J . Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension. Physiol Rev 80: 1337‐1372, 2000.
 91. Harizi H , Juzan M , Grosset C , Rashedi M , Gualde N . Dendritic cells issued in vitro from bone marrow produce PGE(2) that contributes to the immunomodulation induced by antigen‐presenting cells. Cell Immunol 209: 19‐28, 2001.
 92. Hayashi T , Yamada K , Esaki T , Kuzuya M , Satake S , Ishikawa T , Hidaka H , Iguchi A . Estrogen increases endothelial nitric oxide by a receptor‐mediated system. Biochem Biophys Res Commun 214: 847‐855, 1995.
 93. Higuchi S , Ohtsu H , Suzuki H , Shirai H , Frank GD , Eguchi S . Angiotensin II signal transduction through the AT1 receptor: Novel insights into mechanisms and pathophysiology. Clin Sci 112: 417‐428, 2007.
 94. Hirata T , Narumiya S . Prostanoids as regulators of innate and adaptive immunity. Adv Immunol 116: 143‐174, 2012.
 95. Hislop A , Reid L . Normal structure and dimensions of the pulmonary arteries in the rat. J Anat 125: 71‐83, 1978.
 96. Humbert M , Morrell NW , Archer SL , Stenmark KR , MacLean MR , Lang IM , Christman BW , Weir EK , Eickelberg O , Voelkel NF , Rabinovitch M . Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43: S13‐S24, 2004.
 97. Huynh J , Nishimura N , Rana K , Peloquin JM , Califano JP , Montague CR , King MR , Schaffer CB , Reinhart‐King CA . Age‐related intimal stiffening enhances endothelial permeability and leukocyte transmigration. Sci Transl Med 3: 112ra122, 2011.
 98. Imai Y , Kuba K , Rao S , Huan Y , Guo F , Guan B , Yang P , Sarao R , Wada T , Leong‐Poi H , Crackower MA , Fukamizu A , Hui C‐C , Hein L , Uhlig S , Slutsky AS , Jiang C , Penninger JM . Angiotensin‐converting enzyme 2 protects from severe acute lung failure. Nature 436: 112‐116, 2005.
 99. Imig JD . Epoxides and soluble epoxide hydrolase in cardiovascular physiology. Physiol Rev 92: 101‐130, 2012.
 100. Inoue R , Jensen LJ , Jian Z , Shi J , Hai L , Lurie AI , Henriksen FH , Salomonsson M , Morita H , Kawarabayashi Y , Mori M , Mori Y , Ito Y . Synergistic activation of vascular TRPC6 channel by receptor and mechanical stimulation via phospholipase C/diacylglycerol and phospholipase A2/omega‐hydroxylase/20‐HETE pathways. Circ Res 104: 1399‐1409, 2009.
 101. Jacobs ER , Effros RM , Falck JR , Reddy KM , Campbell WB , Zhu D . Airway synthesis of 20‐hydroxyeicosatetraenoic acid: Metabolism by cyclooxygenase to a bronchodilator. Am J Physiol 276: L280‐L288, 1999.
 102. Jang JY , Min JH , Chae YH , Baek JY , Wang SB , Park SJ , Oh GT , Lee S‐H , Ho Y‐S , Chang T‐S . Reactive oxygen species play a critical role in collagen‐induced platelet activation via SHP‐2 oxidation. Antioxid Redox Signal 20: 2528‐2540, .
 103. Jian M‐Y , King JA , Al‐Mehdi A‐B , Liedtke W , Townsley MI . High vascular pressure‐induced lung injury requires P450 epoxygenase‐dependent activation of TRPV4. Am J Respir Cell Mol Biol 38: 386‐392, 2008.
 104. Jin RC , Mahoney CE , Coleman Anderson L , Ottaviano F , Croce K , Leopold JA , Zhang Y‐Y , Tang S‐S , Handy DE , Loscalzo J . Glutathione peroxidase‐3 deficiency promotes platelet‐dependent thrombosis in vivo. Circulation 123: 1963‐1973, 2011.
 105. Keidar S , Kaplan M , Gamliel‐Lazarovich A . ACE2 of the heart: From angiotensin I to angiotensin (1‐7). Cardiovasc Res 73: 463‐469, 2007.
 106. Keserü B , Barbosa‐Sicard E , Popp R , Fisslthaler B , Dietrich A , Gudermann T , Hammock BD , Falck JR , Weissmann N , Busse R , Fleming I . Epoxyeicosatrienoic acids and the soluble epoxide hydrolase are determinants of pulmonary artery pressure and the acute hypoxic pulmonary vasoconstrictor response. FASEB J 22: 4306‐4315, 2008.
 107. Kim S , Iwao H . Molecular and cellular mechanisms of angiotensin II‐mediated cardiovascular and renal diseases. Pharmacol Rev 52: 11‐34, 2000.
 108. Kimura K , Ito M , Amano M , Chihara K , Fukata Y , Nakafuku M , Yamamori B , Feng J , Nakano T , Okawa K , Iwamatsu A , Kaibuchi K . Regulation of myosin phosphatase by Rho and Rho‐associated kinase (Rho‐kinase). Science 273: 245‐248, 1996.
 109. Kizub IV , Strielkov IV , Shaifta Y , Becker S , Prieto‐Lloret J , Snetkov VA , Soloviev AI , Aaronson PI , Ward JPT . Gap junctions support the sustained phase of hypoxic pulmonary vasoconstriction by facilitating calcium sensitization. Cardiovasc Res 99: 404‐411, 2013.
 110. Klein N , Gembardt F , Supé S , Kaestle SM , Nickles H , Erfinanda L , Lei X , Yin J , Wang L , Mertens M , Szaszi K , Walther T , Kuebler WM . Angiotensin‐(1‐7) protects from experimental acute lung injury. Crit Care Med 41: e334‐e343, 2013.
 111. Kohnen SL , Mouithys‐Mickalad AA , Deby‐Dupont GP , Deby CM , Lamy ML , Noels AF . Oxidation of tetrahydrobiopterin by peroxynitrite or oxoferryl species occurs by a radical pathway. Free Radic Res 35: 709‐721, 2001.
 112. Konya V , Üllen A , Kampitsch N , Theiler A , Philipose S , Parzmair GP , Marsche G , Peskar BA , Schuligoi R , Sattler W , Heinemann A . Endothelial E‐type prostanoid 4 receptors promote barrier function and inhibit neutrophil trafficking. J Allergy Clin Immunol 131: 532‐40.e1‐2, 2013.
 113. Koval M , Billaud M , Straub AC , Johnstone SR , Zarbock A , Duling BR , Isakson BE . Spontaneous lung dysfunction and fibrosis in mice lacking connexin 40 and endothelial cell connexin 43. Am J Pathol 178: 2536‐2546, 2011.
 114. Kozłowska H , Baranowska‐Kuczko M , Schlicker E , Kozłowski M , Zakrzeska A , Grzęda E , Malinowska B . EP3 receptor‐mediated contraction of human pulmonary arteries and inhibition of neurogenic tachycardia in pithed rats. Pharmacol Rep 64: 1526‐1536, 2012.
 115. Krötz F , Riexinger T , Buerkle MA , Nithipatikom K , Gloe T , Sohn H‐Y , Campbell WB , Pohl U . Membrane‐potential‐dependent inhibition of platelet adhesion to endothelial cells by epoxyeicosatrienoic acids. Arterioscler Thromb Vasc Biol 24: 595‐600, 2004.
 116. Kubes P , Suzuki M , Granger DN . Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 88: 4651‐4655, 1991.
 117. Kucharewicz I , Chabielska E , Pawlak D , Matys T , Rólkowski R , Buczko W . The antithrombotic effect of angiotensin‐(1‐7) closely resembles that of losartan. J Renin Angiotensin Aldosterone Syst 1: 268‐272, 2000.
 118. Kuebler WM . Selectins revisited: The emerging role of platelets in inflammatory lung disease. J Clin Invest 116: 3106‐3108, 2006.
 119. Kuebler WM . The Janus‐faced regulation of endothelial permeability by cyclic GMP. Am J Physiol Lung Cell Mol Physiol 301: L157‐L160, 2011.
 120. Kuebler WM . Eisenmenger's syndrome: In search of the best vasodilator. Cardiology 126: 252‐254, 2013.
 121. Kuebler WM , Borges J , Sckell A , Kuhnle GE , Bergh K , Messmer K , Goetz AE . Role of L‐selectin in leukocyte sequestration in lung capillaries in a rabbit model of endotoxemia. Am J Respir Crit Care Med 161: 36‐43, 2000.
 122. Kuebler WM , Goetz AE . The marginated pool. Eur Surg Res 34: 92‐100, 2002.
 123. Kuebler WM , Ying X , Bhattacharya J . Pressure‐induced endothelial Ca(2+) oscillations in lung capillaries. Am J Physiol Lung Cell Mol Physiol 282: L917‐L923, 2002.
 124. Kumasaka T , Quinlan WM , Doyle NA , Condon TP , Sligh J , Takei F , Beaudet AL , Bennett CF , Doerschuk CM . Role of the intercellular adhesion molecule‐1(ICAM‐1) in endotoxin‐induced pneumonia evaluated using ICAM‐1 antisense oligonucleotides, anti‐ICAM‐1 monoclonal antibodies, and ICAM‐1 mutant mice. J Clin Invest 97: 2362‐2369, 1996.
 125. Kuschert GS , Coulin F , Power CA , Proudfoot AE , Hubbard RE , Hoogewerf AJ , Wells TN . Glycosaminoglycans interact selectively with chemokines and modulate receptor binding and cellular responses. Biochemistry 38: 12959‐12968, 1999.
 126. Landmesser U , Dikalov S , Price SR , McCann L , Fukai T , Holland SM , Mitch WE , Harrison DG . Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111: 1201‐1209, 2003.
 127. Langleben D , Orfanos SE , Giovinazzo M , Hirsch A , Baron M , Senécal J‐L , Armaganidis A , Catravas JD . Pulmonary capillary endothelial metabolic dysfunction: Severity in pulmonary arterial hypertension related to connective tissue disease versus idiopathic pulmonary arterial hypertension. Arthritis Rheum 58: 1156‐1164, 2008.
 128. Larsen SB , Grove EL , Kristensen SD , Hvas A‐M . Reduced antiplatelet effect of aspirin is associated with low‐grade inflammation in patients with coronary artery disease. Thromb Haemost 109: 920‐929, 2013.
 129. Lenting PJ , Casari C , Christophe OD , Denis CV . von Willebrand factor: The old, the new and the unknown. J Thromb Haemost 10: 2428‐2437, 2012.
 130. Levy BI . How to explain the differences between renin angiotensin system modulators. Am J Hypertens 18: 134S‐141S, 2005.
 131. Li H , Wallerath T , Förstermann U . Physiological mechanisms regulating the expression of endothelial‐type NO synthase. Nitric Oxide 7: 132‐147, 2002.
 132. Lillicrap D . von Willebrand disease: Advances in pathogenetic understanding, diagnosis, and therapy. Blood 122: 3735‐3740, 2013.
 133. Liu F , Mih JD , Shea BS , Kho AT , Sharif AS , Tager AM , Tschumperlin DJ . Feedback amplification of fibrosis through matrix stiffening and COX‐2 suppression. J Cell Biol 190: 693‐706, 2010.
 134. Liu JQ , Erbynn EM , Folz RJ . Chronic hypoxia‐enhanced murine pulmonary vasoconstriction: Role of superoxide and gp91phox. Chest 128: 594S‐596S, 2005.
 135. Liu Y , Zhang Y , Schmelzer K , Lee T‐S , Fang X , Zhu Y , Spector AA , Gill S , Morisseau C , Hammock BD , Shyy JY‐J . The antiinflammatory effect of laminar flow: The role of PPARgamma, epoxyeicosatrienoic acids, and soluble epoxide hydrolase. Proc Natl Acad Sci U S A 102: 16747‐16752, 2005.
 136. Loot AE , Moneke I , Keserü B , Oelze M , Syzonenko T , Daiber A , Fleming I . 11,12‐EET stimulates the association of BK channel α and β(1) subunits in mitochondria to induce pulmonary vasoconstriction. PLoS ONE 7: e46065, 2012.
 137. Lowry JL , Brovkovych V , Zhang Y , Skidgel RA . Endothelial nitric‐oxide synthase activation generates an inducible nitric‐oxide synthase‐like output of nitric oxide in inflamed endothelium. J Biol Chem 288: 4174‐4193, 2013.
 138. Lüscher TF , Vanhoutte PM . The Endothelium. CRC Press, LLC, 1990.
 139. MacRitchie AN , Jun SS , Chen Z , German Z , Yuhanna IS , Sherman TS , Shaul PW . Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ Res 81: 355‐362, 1997.
 140. Mambetsariev I , Tian Y , Wu T , Lavoie T , Solway J , Birukov KG , Birukova AA . Stiffness‐activated GEF‐H1 expression exacerbates LPS‐induced lung inflammation. PLoS ONE 9: e92670, 2014.
 141. Massberg S , Enders G , Leiderer R , Eisenmenger S , Vestweber D , Krombach F , Messmer K . Platelet‐endothelial cell interactions during ischemia/reperfusion: The role of P‐selectin. Blood 92: 507‐515, 1998.
 142. Masuda Y , Miyazaki H , Kondoh M , Watanabe H , Yanagisawa M , Masaki T , Murakami K . Two different forms of endothelin receptors in rat lung. FEBS Lett 257: 208‐210, 1989.
 143. McLaughlin VV , Sitbon O , Badesch DB , Barst RJ , Black C , Galiè N , Rainisio M , Simonneau G , Rubin LJ . Survival with first‐line bosentan in patients with primary pulmonary hypertension. Eur Respir J 25: 244‐249, 2005.
 144. Menden H , Tate E , Hogg N , Sampath V . LPS‐mediated endothelial activation in pulmonary endothelial cells: Role of Nox2‐dependent IKK‐β phosphorylation. Am J Physiol Lung Cell Mol Physiol 304: L445‐L455, 2013.
 145. Meng Y , Yu C‐H , Li W , Li T , Luo W , Huang S , Wu P‐S , Cai S‐X , Li X . Angiotensin‐converting enzyme 2/angiotensin‐(1‐7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF‐κB pathway. Am J Respir Cell Mol Biol (October 29, ). doi: 10.1165/rcmb.2012‐0451OC 50: 723‐736, 2014.
 146. Michaelis UR , Fleming I . From endothelium‐derived hyperpolarizing factor (EDHF) to angiogenesis: Epoxyeicosatrienoic acids (EETs) and cell signaling. Pharmacol Ther 111: 584‐595, 2006.
 147. Michibayashi T . Mechanism of action of hypotensive prostaglandins in patients with essential hypertension. J Smooth Muscle Res 38: 51‐61, 2002.
 148. Middleton J , Neil S , Wintle J , Clark‐Lewis I , Moore H , Lam C , Auer M , Hub E , Rot A . Transcytosis and surface presentation of IL‐8 by venular endothelial cells. Cell 91: 385‐395, 1997.
 149. Middleton J , Patterson AM , Gardner L , Schmutz C , Ashton BA . Leukocyte extravasation: Chemokine transport and presentation by the endothelium. Blood 100: 3853‐3860, 2002.
 150. Mittal M , Roth M , König P , Hofmann S , Dony E , Goyal P , Selbitz A‐C , Schermuly RT , Ghofrani H‐A , Kwapiszewska G , Kummer W , Klepetko W , Hoda MAR , Fink L , Hänze J , Seeger W , Grimminger F , Schmidt HHHW , Weissmann N . Hypoxia‐dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res 101: 258‐267, 2007.
 151. Mizgerd JP . Molecular mechanisms of neutrophil recruitment elicited by bacteria in the lungs. Semin Immunol 14: 123‐132, 2002.
 152. Mizgerd JP , Meek BB , Kutkoski GJ , Bullard DC , Beaudet AL , Doerschuk CM . Selectins and neutrophil traffic: Margination and Streptococcus pneumoniae‐induced emigration in murine lungs. J Exp Med 184: 639‐645, 1996.
 153. Mollnau H , Wendt M , Szöcs K , Lassègue B , Schulz E , Oelze M , Li H , Bodenschatz M , August M , Kleschyov AL , Tsilimingas N , Walter U , Förstermann U , Meinertz T , Griendling K , Münzel T . Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90: E58‐E65, 2002.
 154. Moncada S . Adventures in vascular biology: A tale of two mediators. Philos Trans R Soc Lond, B, Biol Sci 361: 735‐759, 2006.
 155. Moncada S , Higgs EA , Vane JR . Human arterial and venous tissues generate prostacyclin (prostaglandin x), a potent inhibitor of platelet aggregation. Lancet 1: 18‐20, 1977.
 156. Moore TM , Khimenko P , Adkins WK , Miyasaka M , Taylor AE . Adhesion molecules contribute to ischemia and reperfusion‐induced injury in the isolated rat lung. J Appl Physiol 78: 2245‐2252, 1995.
 157. Morgado M , Cairrão E , Santos‐Silva AJ , Verde I . Cyclic nucleotide‐dependent relaxation pathways in vascular smooth muscle. Cell Mol Life Sci 69: 247‐266, 2012.
 158. Moss M , Mannino DM . Race and gender differences in acute respiratory distress syndrome deaths in the United States: An analysis of multiple‐cause mortality data (1979‐ 1996). Crit Care Med 30: 1679‐1685, 2002.
 159. Mustafa AK , Gadalla MM , Snyder SH . Signaling by gasotransmitters. Sci Signal 28;2(68):re2, 2009.
 160. Nataraj C , Thomas DW , Tilley SL , Nguyen MT , Mannon R , Koller BH , Coffman TM . Receptors for prostaglandin E(2) that regulate cellular immune responses in the mouse. J Clin Invest 108: 1229‐1235, 2001.
 161. Node K , Huo Y , Ruan X , Yang B , Spiecker M , Ley K , Zeldin DC , Liao JK . Anti‐inflammatory properties of cytochrome P450 epoxygenase‐derived eicosanoids. Science 285: 1276‐1279, 1999.
 162. Ochoa C , Wu S , Stevens T . New developments in lung endothelial heterogeneity: von Willebrand factor, P‐selectin, and the Weibel‐Palade Body. Semin Thromb Hemost 36: 301‐308, 2010.
 163. Olschewski H , Simonneau G , Galiè N , Higenbottam T , Naeije R , Rubin LJ , Nikkho S , Speich R , Hoeper MM , Behr J , Winkler J , Sitbon O , Popov W , Ghofrani HA , Manes A , Kiely DG , Ewert R , Meyer A , Corris PA , Delcroix M , Gomez‐Sanchez M , Siedentop H , Seeger W , Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 347: 322‐329, 2002.
 164. Olson TS , Singbartl K , Ley K . L‐selectin is required for fMLP‐ but not C5a‐induced margination of neutrophils in pulmonary circulation. Am J Physiol Regul Integr Comp Physiol 282: R1245‐v52, 2002.
 165. Orfanos SE , Armaganidis A , Glynos C , Psevdi E , Kaltsas P , Sarafidou P , Catravas JD , Dafni UG , Langleben D , Roussos C . Pulmonary capillary endothelium‐bound angiotensin‐converting enzyme activity in acute lung injury. Circulation 102: 2011‐2018, 2000.
 166. Orfanos SE , Hirsch AM , Giovinazzo M , Armaganidis A , Catravas JD , Langleben D . Pulmonary capillary endothelial metabolic function in chronic thromboembolic pulmonary hypertension. J Thromb Haemost 6: 1275‐1280, 2008.
 167. Oshima H , Hioki K , Popivanova BK , Oguma K , Van Rooijen N , Ishikawa T‐O , Oshima M . Prostaglandin E2 signaling and bacterial infection recruit tumor‐promoting macrophages to mouse gastric tumors. Gastroenterology 140: 596‐607.e7, 2011.
 168. Paddenberg R , König P , Faulhammer P , Goldenberg A , Pfeil U , Kummer W . Hypoxic vasoconstriction of partial muscular intra‐acinar pulmonary arteries in murine precision cut lung slices. Respir Res 7: 93, 2006.
 169. Palmer RM , Ashton DS , Moncada S . Vascular endothelial cells synthesize nitric oxide from L‐arginine. Nature 333: 664‐666, 1988.
 170. Panés J , Perry MA , Anderson DC , Manning A , Leone B , Cepinskas G , Rosenbloom CL , Miyasaka M , Kvietys PR , Granger DN . Regional differences in constitutive and induced ICAM‐1 expression in vivo. Am J Physiol 269: H1955‐H1964, 1995.
 171. Park SJ , Yoo HY , Earm YE , Kim SJ , Kim JK , Kim SD . Role of arachidonic acid‐derived metabolites in the control of pulmonary arterial pressure and hypoxic pulmonary vasoconstriction in rats. Br J Anaesth 106: 31‐37, 2011.
 172. Parthasarathi K , Ichimura H , Monma E , Lindert J , Quadri S , Issekutz A , Bhattacharya J . Connexin 43 mediates spread of Ca2+‐dependent proinflammatory responses in lung capillaries. J Clin Invest 116: 2193‐2200, 2006.
 173. Paul M , Mehr AP , Kreutz R . Physiology of local renin‐angiotensin systems. Physiol Rev 86(3): 747‐803, 2006.
 174. Pegon JN , Kurdi M , Casari C , Odouard S , Denis CV , Christophe OD , Lenting PJ . Factor VIII and von Willebrand factor are ligands for the carbohydrate‐receptor Siglec‐5. Haematologica 97: 1855‐1863, 2012.
 175. Petri B , Broermann A , Li H , Khandoga AG , Zarbock A , Krombach F , Goerge T , Schneider SW , Jones C , Nieswandt B , Wild MK , Vestweber D . von Willebrand factor promotes leukocyte extravasation. Blood 116: 4712‐4719, 2010.
 176. Pokreisz P , Fleming I , Kiss L , Barbosa‐Sicard E , Fisslthaler B , Falck JR , Hammock BD , Kim I‐H , Szelid Z , Vermeersch P , Gillijns H , Pellens M , Grimminger F , van Zonneveld A‐J , Collen D , Busse R , Janssens S . Cytochrome P450 epoxygenase gene function in hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling. Hypertension 47: 762‐770, 2006.
 177. Pries AR , Kuebler WM . Normal endothelium. Handb Exp Pharmacol 176(1): 1‐40, 2006.
 178. Pulido T , Adzerikho I , Channick RN , Delcroix M , Galiè N , Ghofrani H‐A , Jansa P , Jing Z‐C , Le Brun F‐O , Mehta S , Mittelholzer CM , Perchenet L , Sastry BKS , Sitbon O , Souza R , Torbicki A , Zeng X , Rubin LJ , Simonneau G , SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 369: 809‐818, 2013.
 179. Puri A , McGoon MD , Kushwaha SS . Pulmonary arterial hypertension: Current therapeutic strategies. Nat Clin Pract Cardiovasc Med 4: 319‐329, 2007.
 180. Qin L , Quinlan WM , Doyle NA , Graham L , Sligh JE , Takei F , Beaudet AL , Doerschuk CM . The roles of CD11/CD18 and ICAM‐1 in acute Pseudomonas aeruginosa‐induced pneumonia in mice. J Immunol 157: 5016‐5021, 1996.
 181. Radomski MW , Palmer RM , Moncada S . Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 2: 1057‐1058, 1987.
 182. Rajendran S , Chirkov YY , Campbell DJ , Horowitz JD . Angiotensin‐(1‐7) enhances anti‐aggregatory effects of the nitric oxide donor sodium nitroprusside. J Cardiovasc Pharmacol 46: 459‐463, 2005.
 183. Rajendran S , Chirkov YY , Horowitz JD . Potentiation of platelet responsiveness to nitric oxide by angiotensin‐(1‐7) is associated with suppression of superoxide release. Platelets 18: 158‐164, 2007.
 184. Randriamboavonjy V , Busse R , Fleming I . 20‐HETE‐induced contraction of small coronary arteries depends on the activation of Rho‐kinase. Hypertension 41: 801‐806, 2003.
 185. Reitsma S , Slaaf DW , Vink H , van Zandvoort MAMJ , oude Egbrink MGA . The endothelial glycocalyx: Composition, functions, and visualization. Pflugers Arch 454: 345‐359, 2007.
 186. Rignault S , Haefliger J‐A , Waeber B , Liaudet L , Feihl F . Acute inflammation decreases the expression of connexin 40 in mouse lung. Shock 28: 78‐85, 2007.
 187. Roman RJ . P‐450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 82: 131‐185, 2002.
 188. Rubin LJ , Badesch DB , Barst RJ , Galiè N , Black CM , Keogh A , Pulido T , Frost A , Roux S , Leconte I , Landzberg M , Simonneau G . Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346: 896‐903, 2002.
 189. Rubin LJ , Badesch DB , Fleming TR , Galiè N , Simonneau G , Ghofrani HA , Oakes M , Layton G , Serdarevic‐Pehar M , McLaughlin VV , Barst RJ , SUPER‐2 Study Group. Long‐term treatment with sildenafil citrate in pulmonary arterial hypertension: The SUPER‐2 study. Chest 140: 1274‐1283, 2011.
 190. Rudolph AM , Kurland MD , Auld PA , Paul MH . Effects of vasodilator drugs on normal and serotonin‐constricted pulmonary vessels of the dog. Am J Physiol 197: 617‐623, 1959.
 191. Ruggeri ZM , Zimmerman TS . von Willebrand factor and von Willebrand disease. Blood 70: 895‐904, 1987.
 192. Sader MA , Celermajer DS . Endothelial function, vascular reactivity and gender differences in the cardiovascular system. Cardiovasc Res 53: 597‐604, 2002.
 193. Safari T , Nematbakhsh M , Hilliard LM , Evans RG , Denton KM . Sex differences in the renal vascular response to angiotensin II involves the Mas receptor. Acta Physiol (Oxf) 206: 150‐156, 2012.
 194. Samapati R , Yang Y , Yin J , Stoerger C , Arenz C , Dietrich A , Gudermann T , Adam D , Wu S , Freichel M , Flockerzi V , Uhlig S , Kuebler WM . Lung endothelial Ca2+ and permeability response to platelet‐activating factor is mediated by acid sphingomyelinase and transient receptor potential classical 6. Am J Respir Crit Care Med 185: 160‐170, 2012.
 195. Santos RAS , Simoes e Silva AC , Maric C , Silva DMR , Machado RP , de Buhr I , Heringer‐Walther S , Pinheiro SVB , Lopes MT , Bader M , Mendes EP , Lemos VS , Campagnole‐Santos MJ , Schultheiss H‐P , Speth R , Walther T . Angiotensin‐(1‐7) is an endogenous ligand for the G protein‐coupled receptor Mas. Proc Natl Acad Sci U S A 100: 8258‐8263, 2003.
 196. Schlossmann J , Ammendola A , Ashman K , Zong X , Huber A , Neubauer G , Wang GX , Allescher HD , Korth M , Wilm M , Hofmann F , Ruth P . Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta. Nature 404: 197‐201, 2000.
 197. Schmidt EP , Yang Y , Janssen WJ , Gandjeva A , Perez MJ , Barthel L , Zemans RL , Bowman JC , Koyanagi DE , Yunt ZX , Smith LP , Cheng SS , Overdier KH , Thompson KR , Geraci MW , Douglas IS , Pearse DB , Tuder RM . The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 18: 1217‐1223, 2012.
 198. Seeley EJ , Rosenberg P , Matthay MA . Calcium flux and endothelial dysfunction during acute lung injury: A STIMulating target for therapy. J Clin Invest 123: 1015‐1018, 2013.
 199. Sellers MM , Stallone JN . Sympathy for the devil: The role of thromboxane in the regulation of vascular tone and blood pressure. Am J Physiol Heart Circ Physiol 294: H1978‐H1986, 2008.
 200. Sen CK , Packer L . Antioxidant and redox regulation of gene transcription. FASEB J 10: 709‐720, 1996.
 201. Senba S , Eto M , Yazawa M . Identification of trimeric myosin phosphatase (PP1M) as a target for a novel PKC‐potentiated protein phosphatase‐1 inhibitory protein (CPI17) in porcine aorta smooth muscle. J Biochem 125: 354‐362, 1999.
 202. Shanmugam S , Corvol P , Gasc JM . Angiotensin II type 2 receptor mRNA expression in the developing cardiopulmonary system of the rat. Hypertension 28: 91‐97, 1996.
 203. Shao D , Park JES , Wort SJ . The role of endothelin‐1 in the pathogenesis of pulmonary arterial hypertension. Pharmacol Res 63: 504‐511, 2011.
 204. Shenoy V , Gjymishka A , Jarajapu YP , Qi Y , Afzal A , Rigatto K , Ferreira AJ , Fraga‐Silva RA , Kearns P , Douglas JY , Agarwal D , Mubarak KK , Bradford C , Kennedy WR , Jun JY , Rathinasabapathy A , Bruce E , Gupta D , Cardounel AJ , Mocco J , Patel JM , Francis J , Grant MB , Katovich MJ , Raizada MK . Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. Am J Respir Crit Care Med 187: 648‐657, 2013.
 205. Shenoy V , Qi Y , Katovich MJ , Raizada MK . ACE2, a promising therapeutic target for pulmonary hypertension. Curr Opin Pharmacol 11: 150‐155, 2011.
 206. Shimoda LA , Laurie SS . Vascular remodeling in pulmonary hypertension. J Mol Med 91: 297‐309, 2013.
 207. Siedlecki CA , Lestini BJ , Kottke‐Marchant KK , Eppell SJ , Wilson DL , Marchant RE . Shear‐dependent changes in the three‐dimensional structure of human von Willebrand factor. Blood 88: 2939‐2950, 1996.
 208. Singh B , Fu C , Bhattacharya J . Vascular expression of the alpha(v)beta(3)‐integrin in lung and other organs. Am J Physiol Lung Cell Mol Physiol 278: L217‐L226, 2000.
 209. Siragy HM . The role of the AT2 receptor in hypertension. Am J Hypertens 13: 62S‐67S, 2000.
 210. Society TAP . The American Physiological Society Statement on H.R. 4879. httpwwwthe‐apsorgmmSciencePolicyAboutComments‐LettersHR‐html Sept 4, 2014.
 211. Sorescu GP , Song H , Tressel SL , Hwang J , Dikalov S , Smith DA , Boyd NL , Platt MO , Lassègue B , Griendling KK , Jo H . Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1‐based NADPH oxidase. Circ Res 95: 773‐779, 2004.
 212. Stamler JS , Loh E , Roddy MA , Currie KE , Creager MA . Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation 89: 2035‐2040, 1994.
 213. Steudel W , Ichinose F , Huang PL , Hurford WE , Jones RC , Bevan JA , Fishman MC , Zapol WM . Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene. Circ Res 81: 34‐41, 1997.
 214. Stevens T . Functional and molecular heterogeneity of pulmonary endothelial cells. Proc Am Thorac Soc 8: 453‐457, 2011.
 215. Stevens T , Phan S , Frid MG , Alvarez D , Herzog E , Stenmark KR . Lung vascular cell heterogeneity: Endothelium, smooth muscle, and fibroblasts. Proc Am Thorac Soc 5: 783‐791, 2008.
 216. Stitham J , Midgett C , Martin KA , Hwa J . Prostacyclin: An inflammatory paradox. Front Pharmacol 2: 24, 2011.
 217. Stull JT , Tansey MG , Word RA , Kubota Y , Kamm KE . Myosin light chain kinase phosphorylation: Regulation of the Ca2+ sensitivity of contractile elements. Adv Exp Med Biol 304: 129‐138, 1991.
 218. Sylvester JT , Shimoda LA , Aaronson PI , Ward JPT . Hypoxic pulmonary vasoconstriction. Physiol Rev 92: 367‐520, 2012.
 219. Tabuchi A , Kuebler WM . Endothelium‐platelet interactions in inflammatory lung disease. Vascul Pharmacol 49: 141‐150, 2008.
 220. Tabuchi A , Mertens M , Kuppe H , Pries AR , Kuebler WM . Intravital microscopy of the murine pulmonary microcirculation. J Appl Physiol 104: 338‐346, 2008.
 221. Takahashi Y , Tokuoka S , Masuda T , Hirano Y , Nagao M , Tanaka H , Inagaki N , Narumiya S , Nagai H . Augmentation of allergic inflammation in prostanoid IP receptor deficient mice. Br J Pharmacol 137: 315‐322, 2002.
 222. Tanaka KA , Key NS , Levy JH . Blood coagulation: Hemostasis and thrombin regulation. Anesth Analg 108: 1433‐1446, 2009.
 223. Taniyama Y , Griendling KK . Reactive oxygen species in the vasculature: Molecular and cellular mechanisms. Hypertension 42: 1075‐1081, 2003.
 224. Tarbell JM . Shear stress and the endothelial transport barrier. Cardiovasc Res 87: 320‐330, 2010.
 225. Tate RM , Morris HG , Schroeder WR , Repine JE . Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline‐perfused rabbit lungs. J Clin Invest 74: 608‐613, 1984.
 226. Thodeti CK , Matthews B , Ravi A , Mammoto A , Ghosh K , Bracha AL , Ingber DE . TRPV4 channels mediate cyclic strain‐induced endothelial cell reorientation through integrin‐to‐integrin signaling. Circ Res 104: 1123‐1130, 2009.
 227. True AL , Rahman A , Malik AB . Activation of NF‐kappaB induced by H(2)O(2) and TNF‐alpha and its effects on ICAM‐1 expression in endothelial cells. Am J Physiol Lung Cell Mol Physiol 279: L302‐L311, 2000.
 228. Tuder RM , Cool CD , Geraci MW , Wang J , Abman SH , Wright L , Badesch D , Voelkel NF . Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 159: 1925‐1932, 1999.
 229. Tzao C , Nickerson PA , Russell JA , Gugino SF , Steinhorn RH . Pulmonary hypertension alters soluble guanylate cyclase activity and expression in pulmonary arteries isolated from fetal lambs. Pediatr Pulmonol 31: 97‐105, 2001.
 230. Ueda A , Shimomura M , Ikeda M , Yamaguchi R , Tanishita K . Effect of glycocalyx on shear‐dependent albumin uptake in endothelial cells. Am J Physiol Heart Circ Physiol 287: H2287‐H2294, 2004.
 231. Uhal BD , Li X , Xue A , Gao X , Abdul‐Hafez A . Regulation of alveolar epithelial cell survival by the ACE‐2/angiotensin 1‐7/Mas axis. Am J Physiol Lung Cell Mol Physiol 301: L269‐L274, 2011.
 232. Uhlig S , Yang Y , Waade J , Wittenberg C , Babendreyer A , Kuebler WM . Differential regulation of lung endothelial permeability in vitro and in situ. Cell Physiol Biochem 34: 1‐19, 2014.
 233. Undem C , Rios EJ , Maylor J , Shimoda LA . Endothelin‐1 augments Na+/H+ exchange activity in murine pulmonary arterial smooth muscle cells via Rho kinase. PLoS ONE 7: e46303, 2012.
 234. van Rodijnen WF , Korstjens IJ , Legerstee N , Wee Ter PM , Tangelder G‐J . Direct vasoconstrictor effect of prostaglandin E2 on renal interlobular arteries: Role of the EP3 receptor. Am J Physiol Renal Physiol 292: F1094‐F1101, 2007.
 235. Vane JR . Inhibition of prostaglandin synthesis as a mechanism of action for aspirin‐like drugs. Nature New Biol 231: 232‐235, 1971.
 236. Vink H , Duling BR . Capillary endothelial surface layer selectively reduces plasma solute distribution volume. Am J Physiol Heart Circ Physiol 278: H285‐H289, 2000.
 237. Violi F , Pignatelli P . Platelet oxidative stress and thrombosis. Thromb Res 129: 378‐381, 2012.
 238. Wagner OF , Christ G , Wojta J , Vierhapper H , Parzer S , Nowotny PJ , Schneider B , Waldhäusl W , Binder BR . Polar secretion of endothelin‐1 by cultured endothelial cells. J Biol Chem 267: 16066‐16068, 1992.
 239. Walch L , Labat C , Gascard JP , de Montpreville V , Brink C , Norel X . Prostanoid receptors involved in the relaxation of human pulmonary vessels. Br J Pharmacol 126: 859‐866, 1999.
 240. Wang L , Fuster M , Sriramarao P , Esko JD . Endothelial heparan sulfate deficiency impairs L‐selectin‐ and chemokine‐mediated neutrophil trafficking during inflammatory responses. Nat Immunol 6: 902‐910, 2005.
 241. Wang L , Yin J , Nickles HT , Ranke H , Tabuchi A , Hoffmann J , Tabeling C , Barbosa‐Sicard E , Chanson M , Kwak BR , Shin H‐S , Wu S , Isakson BE , Witzenrath M , de Wit C , Fleming I , Kuppe H , Kuebler WM . Hypoxic pulmonary vasoconstriction requires connexin 40‐mediated endothelial signal conduction. J Clin Invest 122: 4218‐4230, 2012.
 242. Warner TD . Influence of endothelial mediators on the vascular smooth muscle and circulating platelets and blood cells. Int Angiol 15: 93‐99, 1996.
 243. Watanabe H , Vriens J , Prenen J , Droogmans G , Voets T , Nilius B . Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424: 434‐438, 2003.
 244. Waxman AB , Zamanian RT . Pulmonary arterial hypertension: New insights into the optimal role of current and emerging prostacyclin therapies. Am J Cardiol 111: 1A‐16A‐ quiz 17A‐19A, 2013.
 245. Waypa GB , Marks JD , Guzy RD , Mungai PT , Schriewer JM , Dokic D , Ball MK , Schumacker PT . Superoxide generated at mitochondrial complex III triggers acute responses to hypoxia in the pulmonary circulation. Am J Respir Crit Care Med 187: 424‐432, 2013.
 246. Weinbaum S , Tarbell JM , Damiano ER . The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 9: 121‐167, 2007.
 247. Weir EK , Archer SL . Counterpoint: Hypoxic pulmonary vasoconstriction is not mediated by increased production of reactive oxygen species. J Appl Physiol 101: 995‐8– discussion 998, 2006.
 248. Weissmann N , Dietrich A , Fuchs B , Kalwa H , Ay M , Dumitrascu R , Olschewski A , Storch U , Mederos y Schnitzler M , Ghofrani HA , Schermuly RT , Pinkenburg O , Seeger W , Grimminger F , Gudermann T . Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci U S A 103: 19093‐19098, 2006.
 249. Whitman EM , Pisarcik S , Luke T , Fallon M , Wang J , Sylvester JT , Semenza GL , Shimoda LA . Endothelin‐1 mediates hypoxia‐induced inhibition of voltage‐gated K+ channel expression in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 294: L309‐L318, 2008.
 250. Wösten‐van Asperen RM , Lutter R , Haitsma JJ , Merkus MP , van Woensel JB , van der Loos CM , Florquin S , Lachmann B , Bos AP . ACE mediates ventilator‐induced lung injury in rats via angiotensin II but not bradykinin. Eur Respir J 31: 363‐371, 2008.
 251. Wrighton KH . Cell adhesion: The ‘ins’ and “outs” of integrin signalling. Nat Rev Mol Cell Biol 14: 752, 2013.
 252. Xia Y , Fu Z , Hu J , Huang C , Paudel O , Cai S , Liedtke W , Sham JSK . TRPV4 channel contributes to serotonin‐induced pulmonary vasoconstriction and the enhanced vascular reactivity in chronic hypoxic pulmonary hypertension. Am J Physiol, Cell Physiol 305: C704‐C715, 2013.
 253. Xu J , Xie Z , Reece R , Pimental D , Zou M‐H . Uncoupling of endothelial nitric oxidase synthase by hypochlorous acid: Role of NAD(P)H oxidase‐derived superoxide and peroxynitrite. Arterioscler Thromb Vasc Biol 26: 2688‐2695, 2006.
 254. Yan G , Wang Q , Shi H , Han Y , Ma G , Tang C , Gu Y . Regulation of rat intrapulmonary arterial tone by arachidonic acid and prostaglandin E2 during hypoxia. PLoS ONE 8: e73839, 2013.
 255. Yang Y , Yin J , Baumgartner W , Samapati R , Solymosi EA , Reppien E , Kuebler WM , Uhlig S . Platelet‐activating factor reduces endothelial nitric oxide production: Role of acid sphingomyelinase. Eur Respir J 36: 417‐427, 2010.
 256. Yin J , Hoffmann J , Kaestle SM , Neye N , Wang L , Baeurle J , Liedtke W , Wu S , Kuppe H , Pries AR , Kuebler WM . Negative‐feedback loop attenuates hydrostatic lung edema via a cGMP‐dependent regulation of transient receptor potential vanilloid 4. Circ Res 102: 966‐974, 2008.
 257. Yin N , Kaestle S , Yin J , Hentschel T , Pries AR , Kuppe H , Kuebler WM . Inhaled nitric oxide versus aerosolized iloprost for the treatment of pulmonary hypertension with left heart disease. Crit Care Med 37: 980‐986, 2009.
 258. Ying X , Minamiya Y , Fu C , Bhattacharya J . Ca2+ waves in lung capillary endothelium. Circ Res 79: 898‐908, 1996.
 259. Zahler S , Hoffmann A , Gloe T , Pohl U . Gap‐junctional coupling between neutrophils and endothelial cells: A novel modulator of transendothelial migration. J Leukoc Biol 73: 118‐126, 2003.
 260. Zamora CA , Baron DA , Heffner JE . Thromboxane contributes to pulmonary hypertension in ischemia‐reperfusion lung injury. J Appl Physiol 74: 224‐229, 1993.
 261. Zarbock A , Singbartl K , Ley K . Complete reversal of acid‐induced acute lung injury by blocking of platelet‐neutrophil aggregation. J Clin Invest 116: 3211‐3219, 2006.
 262. Zeldin DC , Foley J , Ma J , Boyle JE , Pascual JM , Moomaw CR , Tomer KB , Steenbergen C , Wu S . CYP2J subfamily P450s in the lung: Expression, localization, and potential functional significance. Mol Pharmacol 50: 1111‐1117, 1996.
 263. Zhang L , Cui Y , Geng B , Zeng X , Tang C . 11,12‐Epoxyeicosatrienoic acid activates the L‐arginine/nitric oxide pathway in human platelets. Mol Cell Biochem 308: 51‐56, 2008.
 264. Zhang X , Shan P , Jiang G , Cohn L , Lee PJ . Toll‐like receptor 4 deficiency causes pulmonary emphysema. J Clin Invest 116: 3050‐3059, 2006.
 265. Zhao Y‐Y , Zhao YD , Mirza MK , Huang JH , Potula H‐HSK , Vogel SM , Brovkovych V , Yuan JX‐J , Wharton J , Malik AB . Persistent eNOS activation secondary to caveolin‐1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest 119: 2009‐2018, 2009.
 266. Zhou C , Chen H , King JA , Sellak H , Kuebler WM , Yin J , Townsley MI , Shin H‐S , Wu S . Alpha1G T‐type calcium channel selectively regulates P‐selectin surface expression in pulmonary capillary endothelium. Am J Physiol Lung Cell Mol Physiol 299: L86‐L97, 2010.
 267. Zhou W , Hashimoto K , Goleniewska K , O'Neal JF , Ji S , Blackwell TS , FitzGerald GA , Egan KM , Geraci MW , Peebles RS . Prostaglandin I2 analogs inhibit proinflammatory cytokine production and T cell stimulatory function of dendritic cells. J Immunol 178: 702‐710, 2007.
 268. Zulueta JJ , Yu FS , Hertig IA , Thannickal VJ , Hassoun PM . Release of hydrogen peroxide in response to hypoxia‐reoxygenation: Role of an NAD(P)H oxidase‐like enzyme in endothelial cell plasma membrane. Am J Respir Cell Mol Biol 12: 41‐49, 1995.
 269. Murata T , Ushikubi F , Matsuoka T , Hirata M , Yamasaki A , Sugimoto Y , Ichikawa A , Aze Y , Tanaka T , Yoshida N , Ueno A , Oh‐ishi S , Narumiya S . Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 388: 678‐682, 1997.
 270. Harizi H , Grosset C , Gualde N . Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes. J Leuk Biol 73: 756‐763, 2003.

Related Articles:

Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models
Endothelial and Smooth Muscle Cell Ion Channels in Pulmonary Vasoconstriction and Vascular Remodeling
Adhesion Molecules: Master Controllers of the Circulatory System

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Endothelial Cell Regulation of Pulmonary Vascular Tone, Inflammation, and Coagulation
 

How to Cite

Neil M. Goldenberg, Wolfgang M. Kuebler. Endothelial Cell Regulation of Pulmonary Vascular Tone, Inflammation, and Coagulation. Compr Physiol 2015, 5: 531-559. doi: 10.1002/cphy.c140024