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Receptor-Mediated Signal Transduction and Cell Signaling

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Textbook of Pulmonary Vascular Disease

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Abstract

The maintenance of low resistance, pressure, and tone in the pulmonary circulation is dependent on the interaction of circulating and locally produced vasomodulatory regulators; many such vasoactive mediators act via receptor-mediated signaling pathways. Many types of receptors that regulate pulmonary vascular tone are expressed on the plasma membrane of cells, although vasomotor activity is also influenced by intracellular receptors, such as calcium-release receptors and receptors that regulate transcription (e.g., steroid hormone receptors). The pulmonary vasculature expresses a wide variety of receptor classes and subtypes that facilitate the interaction of cells of the pulmonary circulation with their extracellular environment (hormones, neurotransmitters, and other factors in the extracellular milieu play key roles in modifying blood flow under both physiological and patho-physiological conditions). One can identify such receptors by assessing the binding of radioligands, molecular cloning and expression studies, antisense approaches, and/or by conducting studies with transgenic or knockout animals. Receptor-mediated signaling in the pulmonary circulation changes with development and disease, is highly species specific, cell-type specific, and often depends on an intact endothelium. Moreover, the accessibility of plasma membrane receptors for neurotransmitters and hormones from the extracellular environment makes them excellent drug targets. The major classes of membrane receptors that regulate pulmonary vascular tone are G-protein-coupled receptors, ligand-gated ion channels, and receptor protein kinases [receptor tyrosine kinase and serine/threonine kinase receptors]. This chapter provides an overview of signaling by cell-surface receptors in the pulmonary circulation and highlights mediators whose activation regulates pulmonary vascular development, tone, and permeability.

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References

  1. Barnes PJ, Liu SF (1995) Regulation of pulmonary vascular tone. Pharmacol Rev 47:87–131

    PubMed  CAS  Google Scholar 

  2. Humbert M, Morrell NW, Archer SL et al (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43:13S–24S

    PubMed  CAS  Google Scholar 

  3. Rabinovitch M (2008) Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 118:2372–2379

    PubMed  CAS  Google Scholar 

  4. Haworth SG, Hislop AA (1983) Pulmonary vascular development: normal values of peripheral vascular structure. Am J Cardiol 52:578–583

    PubMed  CAS  Google Scholar 

  5. Dupre DJ, Robitaille M, Rebois RV, Hebert TE (2009) The role of Gbetagamma subunits in the organization, assembly, and function of GPCR signaling complexes. Annu Rev Pharmacol Toxicol 49:31–56

    PubMed  CAS  Google Scholar 

  6. Marinissen MJ, Gutkind JS (2001) G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 22:368–376

    PubMed  CAS  Google Scholar 

  7. Tang CM, Insel PA (2004) GPCR expression in the heart; “new” receptors in myocytes and fibroblasts. Trends Cardiovasc Med 14:94–99

    PubMed  CAS  Google Scholar 

  8. Milligan G, Kostenis E (2006) Heterotrimeric G-proteins: a short history. Br J Pharmacol 147(Suppl 1):S46–S55

    PubMed  CAS  Google Scholar 

  9. Rebois RV, Warner DR, Basi NS (1997) Does subunit dissociation necessarily accompany the activation of all heterotrimeric G proteins? Cell Signal 9:141–151

    PubMed  CAS  Google Scholar 

  10. Ross EM, Wilkie TM (2000) GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem 69:795–827

    PubMed  CAS  Google Scholar 

  11. Tang KM, Wang GR, Lu P et al (2003) Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med 9:1506–1512

    PubMed  CAS  Google Scholar 

  12. Ostrom RS, Post SR, Insel PA (2000) Stoichiometry and compartmentation in G protein-coupled receptor signaling: implications for therapeutic interventions involving G(s). J Pharmacol Exp Ther 294:407–412

    PubMed  CAS  Google Scholar 

  13. Malbon CC, Tao J, Wang HY (2004) AKAPs (A-kinase anchoring proteins) and molecules that compose their G-protein-coupled receptor signalling complexes. Biochem J 379:1–9

    PubMed  CAS  Google Scholar 

  14. Marchese A, Paing MM, Temple BR, Trejo J (2008) G protein-coupled receptor sorting to endosomes and lysosomes. Annu Rev Pharmacol Toxicol 48:601–629

    PubMed  CAS  Google Scholar 

  15. Patel HH, Murray F, Insel PA (2008) Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol 48:359–391

    PubMed  CAS  Google Scholar 

  16. Hall RA, Ostedgaard LS, Premont RT et al (1998) A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins. Proc Natl Acad Sci U S A 95:8496–8501

    PubMed  CAS  Google Scholar 

  17. Park DS, Cohen AW, Frank PG et al (2003) Caveolin-1 null (-/-) mice show dramatic reductions in life span. Biochemistry 42:15124–15131

    PubMed  CAS  Google Scholar 

  18. Xiao RP (2001) Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G(s) and G(i) proteins. Sci STKE 2001:RE15

    PubMed  CAS  Google Scholar 

  19. Meszaros JG, Gonzalez AM, Endo-Mochizuki Y, Villegas S, Villarreal F, Brunton LL (2000) Identification of G protein-coupled signaling pathways in cardiac fibroblasts: cross talk between G(q) and G(s). Am J Physiol Cell Physiol 278:C154–C162

    PubMed  CAS  Google Scholar 

  20. Baker JG, Hill SJ (2007) Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates. Trends Pharmacol Sci 28:374–381

    PubMed  CAS  Google Scholar 

  21. Kenakin T (2003) Ligand-selective receptor conformations revisited: the promise and the problem. Trends Pharmacol Sci 24:346–354

    PubMed  CAS  Google Scholar 

  22. Milligan G, Smith NJ (2007) Allosteric modulation of heterodimeric G-protein-coupled receptors. Trends Pharmacol Sci 28:615–620

    PubMed  CAS  Google Scholar 

  23. Regard JB, Sato IT, Coughlin SR (2008) Anatomical profiling of G protein-coupled receptor expression. Cell 135:561–571

    PubMed  CAS  Google Scholar 

  24. Bonvallet ST, Zamora MR, Hasunuma K et al (1994) BQ123, an ETA-receptor antagonist, attenuates hypoxic pulmonary hypertension in rats. Am J Physiol 266:H1327–H1331

    PubMed  CAS  Google Scholar 

  25. Morrell NW, Morris KG, Stenmark KR (1995) Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension. Am J Physiol 269:H1186–H1194

    PubMed  CAS  Google Scholar 

  26. Creighton JR, Masada N, Cooper DM, Stevens T (2003) Coordinate regulation of membrane cAMP by Ca2+-inhibited adenylyl cyclase and phosphodiesterase activities. Am J Physiol Lung Cell Mol Physiol 284:L100–L107

    PubMed  CAS  Google Scholar 

  27. Jourdan KB, Mason NA, Long L, Philips PG, Wilkins MR, Morrell NW (2001) Characterization of adenylyl cyclase isoforms in rat peripheral pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 280:L1359–L1369

    PubMed  CAS  Google Scholar 

  28. Murray F, Patel HH, Suda RY et al (2007) Expression and activity of cAMP phosphodiesterase isoforms in pulmonary artery smooth muscle cells from patients with pulmonary hypertension: role for PDE1. Am J Physiol Lung Cell Mol Physiol 292:L294–L303

    PubMed  CAS  Google Scholar 

  29. Bos JL (2006) Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci 31:680–686

    PubMed  CAS  Google Scholar 

  30. Kassel KM, Wyatt TA, Panettieri RA Jr, Toews ML (2008) Inhibition of human airway smooth muscle cell proliferation by beta 2-adrenergic receptors and cAMP is PKA independent: evidence for EPAC involvement. Am J Physiol Lung Cell Mol Physiol 294:L131–L138

    PubMed  CAS  Google Scholar 

  31. McConnachie G, Langeberg LK, Scott JD (2006) AKAP signaling complexes: getting to the heart of the matter. Trends Mol Med 12:317–323

    PubMed  CAS  Google Scholar 

  32. Bradbury DA, Newton R, Zhu YM, El-Haroun H, Corbett L, Knox AJ (2003) Cyclooxygenase-2 induction by bradykinin in human pulmonary artery smooth muscle cells is mediated by the cyclic AMP response element through a novel autocrine loop involving endogenous prostaglandin E2, E-prostanoid 2 (EP2), and EP4 receptors. J Biol Chem 278:49954–49964

    PubMed  CAS  Google Scholar 

  33. Mayr B, Montminy M (2001) Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2:599–609

    PubMed  CAS  Google Scholar 

  34. Adamson RH, Liu B, Fry GN, Rubin LL, Curry FE (1998) Microvascular permeability and number of tight junctions are modulated by cAMP. Am J Physiol 274:H1885–H1894

    PubMed  CAS  Google Scholar 

  35. Bolotina VM, Najibi S, Palacino JJ, Pagano PJ, Cohen RA (1994) Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368:850–853

    PubMed  CAS  Google Scholar 

  36. Ichiki T, Usui M, Kato M et al (1998) Downregulation of ­angiotensin II type 1 receptor gene transcription by nitric oxide. Hypertension 31:342–348

    PubMed  CAS  Google Scholar 

  37. Baertschi AJ, Hausmaninger C, Walsh RS, Mentzer RM Jr, Wyatt DA, Pence RA (1986) Hypoxia-induced release of atrial natriuretic factor (ANF) from the isolated rat and rabbit heart. Biochem Biophys Res Commun 140:427–433

    PubMed  CAS  Google Scholar 

  38. Simon A, Harrington EO, Liu GX, Koren G, Choudhary G (2009) Mechanism of C-type natriuretic peptide-induced endothelial cell hyperpolarization. Am J Physiol Lung Cell Mol Physiol 296:L248–L256

    PubMed  CAS  Google Scholar 

  39. Wu S, Moore TM, Brough GH et al (2000) Cyclic nucleotide-gated channels mediate membrane depolarization following activation of store-operated calcium entry in endothelial cells. J Biol Chem 275:18887–18896

    PubMed  CAS  Google Scholar 

  40. Ward JP, Knock GA, Snetkov VA, Aaronson PI (2004) Protein kinases in vascular smooth muscle tone–role in the pulmonary vasculature and hypoxic pulmonary vasoconstriction. Pharmacol Ther 104:207–231

    PubMed  CAS  Google Scholar 

  41. Vogt S, Grosse R, Schultz G, Offermanns S (2003) Receptor-dependent RhoA activation in G12/G13-deficient cells: genetic evidence for an involvement of Gq/G11. J Biol Chem 278:28743–28749

    PubMed  CAS  Google Scholar 

  42. Sah VP, Seasholtz TM, Sagi SA, Brown JH (2000) The role of Rho in G protein-coupled receptor signal transduction. Annu Rev Pharmacol Toxicol 40:459–489

    PubMed  CAS  Google Scholar 

  43. Riobo NA, Manning DR (2005) Receptors coupled to heterotrimeric G proteins of the G12 family. Trends Pharmacol Sci 26:146–154

    PubMed  CAS  Google Scholar 

  44. Gohla A, Schultz G, Offermanns S (2000) Role for G(12)/G(13) in agonist-induced vascular smooth muscle cell contraction. Circ Res 87:221–227

    PubMed  CAS  Google Scholar 

  45. Gu JL, Muller S, Mancino V, Offermanns S, Simon MI (2002) Interaction of G alpha(12) with G alpha(13) and G alpha(q) signaling pathways. Proc Natl Acad Sci U S A 99:9352–9357

    PubMed  CAS  Google Scholar 

  46. Morello F, Perino A, Hirsch E (2009) Phosphoinositide 3-kinase signalling in the vascular system. Cardiovasc Res 82(2):261–271

    Google Scholar 

  47. Krick S, Hanze J, Eul B et al (2005) Hypoxia-driven proliferation of human pulmonary artery fibroblasts: cross-talk between HIF-1alpha and an autocrine angiotensin system. FASEB J 19:857–859

    PubMed  CAS  Google Scholar 

  48. Boe J, Simonsson BG (1980) Adrenergic receptors and sympathetic agents in isolated human pulmonary arteries. Eur J Respir Dis 61:195–202

    PubMed  CAS  Google Scholar 

  49. Hyman AL, Nandiwada P, Knight DS, Kadowitz PJ (1981) Pulmonary vasodilator responses to catecholamines and sympathetic nerve stimulation in the cat. Evidence that vascular beta-2 adrenoreceptors are innervated. Circ Res 48:407–415

    PubMed  CAS  Google Scholar 

  50. Pourageaud F, Leblais V, Bellance N, Marthan R, Muller B (2005) Role of beta2-adrenoceptors (beta-AR), but not beta1-, beta3-AR and endothelial nitric oxide, in beta-AR-mediated relaxation of rat intrapulmonary artery. Naunyn Schmiedebergs Arch Pharmacol 372:14–23

    PubMed  CAS  Google Scholar 

  51. Leblais V, Delannoy E, Fresquet F et al (2008) beta-adrenergic relaxation in pulmonary arteries: preservation of the endothelial nitric oxide-dependent beta2 component in pulmonary hypertension. Cardiovasc Res 77:202–210

    PubMed  CAS  Google Scholar 

  52. Hyman AL, Lippton HL, Kadowitz PJ (1986) Nature of alpha 1 and postjunctional alpha 2 adrenoceptors in the pulmonary vascular bed. Fed Proc 45:2336–2340

    PubMed  CAS  Google Scholar 

  53. Salvi SS (1999) Alpha1-adrenergic hypothesis for pulmonary hypertension. Chest 115:1708–1719

    PubMed  CAS  Google Scholar 

  54. Minneman KP (1988) Alpha 1-adrenergic receptor subtypes, inositol phosphates, and sources of cell Ca2+. Pharmacol Rev 40:87–119

    PubMed  CAS  Google Scholar 

  55. Takizawa T, Hara Y, Saito T, Masuda Y, Nakaya H (1996) alpha 1-Adrenoceptor stimulation partially inhibits ATP-sensitive K+ current in guinea pig ventricular cells: attenuation of the action potential shortening induced by hypoxia and K+ channel openers. J Cardiovasc Pharmacol 28:799–808

    PubMed  CAS  Google Scholar 

  56. Dinh-Xuan AT, Pepke-Zaba J, Butt AY, Cremona G, Higenbottam TW (1993) Impairment of pulmonary-artery endothelium-­dependent relaxation in chronic obstructive lung disease is not due to dysfunction of endothelial cell membrane receptors nor to L-arginine deficiency. Br J Pharmacol 109:587–591

    PubMed  CAS  Google Scholar 

  57. Eckhart AD, Zhu Z, Arendshorst WJ, Faber JE (1996) Oxygen modulates alpha 1B-adrenergic receptor gene expression by arterial but not venous vascular smooth muscle. Am J Physiol 271:H1599–H1608

    PubMed  CAS  Google Scholar 

  58. Hulme EC, Birdsall NJ, Buckley NJ (1990) Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol 30:633–673

    PubMed  CAS  Google Scholar 

  59. Hyman AL, Kadowitz PJ (1989) Influence of tone on responses to acetylcholine in the rabbit pulmonary vascular bed. J Appl Physiol 67:1388–1394

    PubMed  CAS  Google Scholar 

  60. Greenberg B, Rhoden K, Barnes PJ (1987) Endothelium-dependent relaxation of human pulmonary arteries. Am J Physiol 252:H434–H438

    PubMed  CAS  Google Scholar 

  61. Norel X, Walch L, Costantino M et al (1996) M1 and M3 muscarinic receptors in human pulmonary arteries. Br J Pharmacol 119:149–157

    PubMed  CAS  Google Scholar 

  62. el-Kashef H, Catravas JD (1991) The nature of muscarinic receptor subtypes mediating pulmonary vasoconstriction in the rabbit. Pulm Pharmacol 4:8–19

    Google Scholar 

  63. Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797

    PubMed  CAS  Google Scholar 

  64. McCormack DG, Barnes PJ, Evans TW (1989) Purinoceptors in the pulmonary circulation of the rat and their role in hypoxic vasoconstriction. Br J Pharmacol 98:367–372

    PubMed  CAS  Google Scholar 

  65. Broadley KJ, Maddock HL (1996) P1-purinoceptor-mediated vasodilatation and vasoconstriction in hypoxia. J Auton Pharmacol 16:363–366

    PubMed  CAS  Google Scholar 

  66. El-Kashef H, Elmazar MM, Al-Shabanah OA, Al-Bekairi AM (1999) Effect of adenosine on pulmonary circulation of rabbits. Gen Pharmacol 32:307–313

    PubMed  CAS  Google Scholar 

  67. Dawicki DD, Chatterjee D, Wyche J, Rounds S (1997) Extracellular ATP and adenosine cause apoptosis of pulmonary artery endothelial cells. Am J Physiol 273:L485–L494

    PubMed  CAS  Google Scholar 

  68. Chootip K, Ness KF, Wang Y, Gurney AM, Kennedy C (2002) Regional variation in P2 receptor expression in the rat pulmonary arterial circulation. Br J Pharmacol 137:637–646

    PubMed  CAS  Google Scholar 

  69. Liu SF, McCormack DG, Evans TW, Barnes PJ (1989) Evidence for two P2-purinoceptor subtypes in human small pulmonary arteries. Br J Pharmacol 98:1014–1020

    PubMed  CAS  Google Scholar 

  70. Konduri GG, Bakhutashvili I, Frenn R, Chandrasekhar I, Jacobs ER, Khanna AK (2004) P2Y purine receptor responses and expression in the pulmonary circulation of juvenile rabbits. Am J Physiol Heart Circ Physiol 287:H157–H164

    PubMed  CAS  Google Scholar 

  71. Chootip K, Gurney AM, Kennedy C (2005) Multiple P2Y receptors couple to calcium-dependent, chloride channels in smooth muscle cells of the rat pulmonary artery. Respir Res 6:124

    PubMed  Google Scholar 

  72. Luckhoff A, Busse R (1986) Increased free calcium in endothelial cells under stimulation with adenine nucleotides. J Cell Physiol 126:414–420

    PubMed  CAS  Google Scholar 

  73. Gerasimovskaya EV, Tucker DA, Weiser-Evans M et al (2005) Extracellular ATP-induced proliferation of adventitial fibroblasts requires phosphoinositide 3-kinase, Akt, mammalian target of rapamycin, and p70 S6 kinase signaling pathways. J Biol Chem 280:1838–1848

    PubMed  CAS  Google Scholar 

  74. Barth K, Kasper M (2009) Membrane compartments and purinergic signalling: occurrence and function of P2X receptors in lung. FEBS J 276:341–353

    PubMed  CAS  Google Scholar 

  75. McMillan MR, Burnstock G, Haworth SG (1999) Vasoconstriction of intrapulmonary arteries to P2-receptor nucleotides in normal and pulmonary hypertensive newborn piglets. Br J Pharmacol 128:549–555

    PubMed  CAS  Google Scholar 

  76. Yamamoto K, Sokabe T, Ohura N, Nakatsuka H, Kamiya A, Ando J (2003) Endogenously released ATP mediates shear stress-induced Ca2+ influx into pulmonary artery endothelial cells. Am J Physiol Heart Circ Physiol 285:H793–H803

    PubMed  CAS  Google Scholar 

  77. Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ (2004) Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 43:62S–67S

    PubMed  CAS  Google Scholar 

  78. McCulloch KM, Docherty C, MacLean MR (1998) Endothelin receptors mediating contraction of rat and human pulmonary resistance arteries: effect of chronic hypoxia in the rat. Br J Pharmacol 123:1621–1630

    PubMed  CAS  Google Scholar 

  79. McCulloch KM, MacLean MR (1995) EndothelinB receptor-mediated contraction of human and rat pulmonary resistance arteries and the effect of pulmonary hypertension on endothelin responses in the rat. J Cardiovasc Pharmacol 26(Suppl 3):S169–S176

    PubMed  CAS  Google Scholar 

  80. Dupuis J, Jasmin JF, Prie S, Cernacek P (2000) Importance of local production of endothelin-1 and of the ET(B)Receptor in the regulation of pulmonary vascular tone. Pulm Pharmacol Ther 13:135–140

    PubMed  CAS  Google Scholar 

  81. Sauvageau S, Thorin E, Caron A, Dupuis J (2007) Endothelin-1-induced pulmonary vasoreactivity is regulated by ET(A) and ET(B) receptor interactions. J Vasc Res 44:375–381

    PubMed  CAS  Google Scholar 

  82. Seo B, Oemar BS, Siebenmann R, von Segesser L, Luscher TF (1994) Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 89:1203–1208

    PubMed  CAS  Google Scholar 

  83. Davie N, Haleen SJ, Upton PD et al (2002) ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 165:398–405

    PubMed  Google Scholar 

  84. LaDouceur DM, Flynn MA, Keiser JA, Reynolds E, Haleen SJ (1993) ETA and ETB receptors coexist on rabbit pulmonary artery vascular smooth muscle mediating contraction. Biochem Biophys Res Commun 196:209–215

    PubMed  CAS  Google Scholar 

  85. MacLean MR, McCulloch KM, Baird M (1994) Endothelin ETA- and ETB-receptor-mediated vasoconstriction in rat pulmonary arteries and arterioles. J Cardiovasc Pharmacol 23:838–845

    PubMed  CAS  Google Scholar 

  86. Simonson MS, Herman WH (1993) Protein kinase C and protein tyrosine kinase activity contribute to mitogenic signaling by endothelin-1. Cross-talk between G protein-coupled receptors and pp 60c-src. J Biol Chem 268:9347–9357

    PubMed  CAS  Google Scholar 

  87. Tang B, Li Y, Nagaraj C et al (2009) Endothelin-1 inhibits background two-pore domain channel TASK-1 in primary human pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 41(4):476–483

    PubMed  CAS  Google Scholar 

  88. Zhang XF, Iwamuro Y, Enoki T et al (1999) Pharmacological characterization of Ca2+ entry channels in endothelin-1-induced contraction of rat aorta using LOE 908 and SK&F 96365. Br J Pharmacol 127:1388–1398

    PubMed  CAS  Google Scholar 

  89. Homma N, Nagaoka T, Morio Y et al (2007) Endothelin-1 and serotonin are involved in activation of RhoA/Rho kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation. J Cardiovasc Pharmacol 50:697–702

    PubMed  CAS  Google Scholar 

  90. Janakidevi K, Fisher MA, Del Vecchio PJ, Tiruppathi C, Figge J, Malik AB (1992) Endothelin-1 stimulates DNA synthesis and proliferation of pulmonary artery smooth muscle cells. Am J Physiol 263:C1295–C1301

    PubMed  CAS  Google Scholar 

  91. Giaid A, Yanagisawa M, Langleben D et al (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328:1732–1739

    PubMed  CAS  Google Scholar 

  92. Dempsie Y, MacLean MR (2008) Pulmonary hypertension: therapeutic targets within the serotonin system. Br J Pharmacol 155:455–462

    PubMed  CAS  Google Scholar 

  93. Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554

    PubMed  CAS  Google Scholar 

  94. Launay JM, Herve P, Peoc’h K et al (2002) Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med 8:1129–1135

    PubMed  CAS  Google Scholar 

  95. Morecroft I, MacLean MR (1998) 5-hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries. Br J Pharmacol 125:69–78

    PubMed  CAS  Google Scholar 

  96. MacLean MR, Clayton RA, Templeton AG, Morecroft I (1996) Evidence for 5-HT1-like receptor-mediated vasoconstriction in human pulmonary artery. Br J Pharmacol 119:277–282

    PubMed  CAS  Google Scholar 

  97. MacLean MR, Sweeney G, Baird M, McCulloch KM, Houslay M, Morecroft I (1996) 5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats. Br J Pharmacol 119:917–930

    PubMed  CAS  Google Scholar 

  98. MacLean MR, Clayton RA, Hillis SW, McIntyre PD, Peacock AJ, Templeton AG (1994) 5-HT1-receptor-mediated vasoconstriction in bovine isolated pulmonary arteries: influences of vascular endothelium and tone. Pulm Pharmacol 7:65–72

    PubMed  CAS  Google Scholar 

  99. Guignabert C, Raffestin B, Benferhat R et al (2005) Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation 111:2812–2819

    PubMed  CAS  Google Scholar 

  100. Lawrie A, Spiekerkoetter E, Martinez EC et al (2005) Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease. Circ Res 97:227–235

    PubMed  CAS  Google Scholar 

  101. Liu Y, Ren W, Warburton R, Toksoz D, Fanburg BL (2009) Serotonin induces Rho/ROCK-dependent activation of Smads 1/5/8 in pulmonary artery smooth muscle cells. FASEB J 23(7):2299–2306

    PubMed  CAS  Google Scholar 

  102. Sweeney G, Templeton A, Clayton RA et al (1995) Contractile responses to sumatriptan in isolated bovine pulmonary artery rings: relationship to tone and cyclic nucleotide levels. J Cardiovasc Pharmacol 26:751–760

    PubMed  CAS  Google Scholar 

  103. Christman BW (1998) Lipid mediator dysregulation in primary pulmonary hypertension. Chest 114:205S–207S

    PubMed  CAS  Google Scholar 

  104. Shaul PW, Kinane B, Farrar MA, Buja LM, Magness RR (1991) Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat. J Clin Invest 88:447–455

    PubMed  CAS  Google Scholar 

  105. Wharton J, Davie N, Upton PD, Yacoub MH, Polak JM, Morrell NW (2000) Prostacyclin analogues differentially inhibit growth of distal and proximal human pulmonary artery smooth muscle cells. Circulation 102:3130–3136

    PubMed  CAS  Google Scholar 

  106. Geraci MW, Gao B, Shepherd DC et al (1999) Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest 103:1509–1515

    PubMed  CAS  Google Scholar 

  107. O’Callaghan DS, Gaine SP (2007) Combination therapy and new types of agents for pulmonary arterial hypertension. Clin Chest Med 28:169–185; ix

    Google Scholar 

  108. Snetkov VA, Knock GA, Baxter L, Thomas GD, Ward JP, Aaronson PI (2006) Mechanisms of the prostaglandin F2alpha-induced rise in [Ca2+]i in rat intrapulmonary arteries. J Physiol 571:147–163

    PubMed  CAS  Google Scholar 

  109. Cogolludo A, Moreno L, Bosca L, Tamargo J, Perez-Vizcaino F (2003) Thromboxane A2-induced inhibition of voltage-gated K+ channels and pulmonary vasoconstriction: role of protein kinase Czeta. Circ Res 93:656–663

    PubMed  CAS  Google Scholar 

  110. Komarova YA, Mehta D, Malik AB (2007) Dual regulation of endothelial junctional permeability. Sci STKE 2007:re8

    PubMed  Google Scholar 

  111. Feistritzer C, Riewald M (2005) Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 105:3178–3184

    PubMed  CAS  Google Scholar 

  112. Konstantoulaki M, Kouklis P, Malik AB (2003) Protein kinase C modifications of VE-cadherin, p120, and beta-catenin contribute to endothelial barrier dysregulation induced by thrombin. Am J Physiol Lung Cell Mol Physiol 285:L434–L442

    PubMed  CAS  Google Scholar 

  113. Nguyen QD, Faivre S, Bruyneel E et al (2002) RhoA- and RhoD-dependent regulatory switch of Galpha subunit signaling by PAR-1 receptors in cellular invasion. FASEB J 16:565–576

    PubMed  CAS  Google Scholar 

  114. Sacks RS, Firth AL, Remillard CV et al (2008) Thrombin-mediated increases in cytosolic [Ca2+] involve different mechanisms in human pulmonary artery smooth muscle and endothelial cells. Am J Physiol Lung Cell Mol Physiol 295:L1048–L1055

    PubMed  CAS  Google Scholar 

  115. Shikata Y, Birukov KG, Garcia JG (2003) S1P induces FA remodeling in human pulmonary endothelial cells: role of Rac, GIT1, FAK, and paxillin. J Appl Physiol 94:1193–1203

    PubMed  CAS  Google Scholar 

  116. Garcia JG, Liu F, Verin AD et al (2001) Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J Clin Invest 108:689–701

    PubMed  CAS  Google Scholar 

  117. Mehta D, Konstantoulaki M, Ahmmed GU, Malik AB (2005) Sphingosine 1-phosphate-induced mobilization of intracellular Ca2+ mediates rac activation and adherens junction assembly in endothelial cells. J Biol Chem 280:17320–17328

    PubMed  CAS  Google Scholar 

  118. Ancellin N, Hla T (1999) Differential pharmacological properties and signal transduction of the sphingosine 1-phosphate receptors EDG-1, EDG-3, and EDG-5. J Biol Chem 274:18997–19002

    PubMed  CAS  Google Scholar 

  119. Singleton PA, Dudek SM, Chiang ET, Garcia JG (2005) 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

    PubMed  CAS  Google Scholar 

  120. Brown MD, Sacks DB (2009) Protein scaffolds in MAP kinase signalling. Cell Signal 21:462–469

    PubMed  CAS  Google Scholar 

  121. Pearson G, Robinson F (2001) Beers Gibson T, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:153–183

    PubMed  CAS  Google Scholar 

  122. Yamboliev IA, Hruby A, Gerthoffer WT (1998) Endothelin-1 activates MAP kinases and c-Jun in pulmonary artery smooth muscle. Pulm Pharmacol Ther 11:205–208

    PubMed  CAS  Google Scholar 

  123. Lai K, Wang H, Lee WS, Jain MK, Lee ME, Haber E (1996) Mitogen-activated protein kinase phosphatase-1 in rat arterial smooth muscle cell proliferation. J Clin Invest 98:1560–1567

    PubMed  CAS  Google Scholar 

  124. Denhardt DT (1996) Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling. Biochem J 318(Pt 3):729–747

    PubMed  CAS  Google Scholar 

  125. Yamabhai M, Anderson RG (2002) Second cysteine-rich region of epidermal growth factor receptor contains targeting information for caveolae/rafts. J Biol Chem 277:24843–24846

    PubMed  CAS  Google Scholar 

  126. Stenmark KR, Abman SH (2005) Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. Annu Rev Physiol 67:623–661

    PubMed  CAS  Google Scholar 

  127. Carmeliet P, Ferreira V, Breier G et al (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439

    PubMed  CAS  Google Scholar 

  128. He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB (1999) Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem 274:25130–25135

    PubMed  CAS  Google Scholar 

  129. Fontana J, Fulton D, Chen Y et al (2002) Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release. Circ Res 90:866–873

    PubMed  CAS  Google Scholar 

  130. Campbell AI, Zhao Y, Sandhu R, Stewart DJ (2001) Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension. Circulation 104:2242–2248

    PubMed  CAS  Google Scholar 

  131. Hirschi KK, Rohovsky SA, Beck LH, Smith SR, D’Amore PA (1999) Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. Circ Res 84:298–305

    PubMed  CAS  Google Scholar 

  132. Schermuly RT, Dony E, Ghofrani HA et al (2005) Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115:2811–2821

    PubMed  CAS  Google Scholar 

  133. Merklinger SL, Jones PL, Martinez EC, Rabinovitch M (2005) Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112:423–431

    PubMed  CAS  Google Scholar 

  134. Yu Y, Sweeney M, Zhang S et al (2003) PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am J Physiol Cell Physiol 284:C316–C330

    PubMed  CAS  Google Scholar 

  135. Garat CV, Fankell D, Erickson PF et al (2006) Platelet-derived growth factor BB induces nuclear export and proteasomal degradation of CREB via phosphatidylinositol 3-kinase/Akt signaling in pulmonary artery smooth muscle cells. Mol Cell Biol 26:4934–4948

    PubMed  CAS  Google Scholar 

  136. Davis BN, Hilyard AC, Nguyen PH, Lagna G, Hata A (2009) Induction of microRNA-221 by platelet-derived growth factor signaling is critical for modulation of vascular smooth muscle phenotype. J Biol Chem 284:3728–3738

    PubMed  CAS  Google Scholar 

  137. Izikki M, Guignabert C, Fadel E et al (2009) Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 119:512–523

    PubMed  CAS  Google Scholar 

  138. Schmierer B, Hill CS (2007) TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8:970–982

    PubMed  CAS  Google Scholar 

  139. Goumans MJ, Liu Z, ten Dijke P (2009) TGF-beta signaling in vascular biology and dysfunction. Cell Res 19:116–127

    PubMed  CAS  Google Scholar 

  140. Zhang YE (2009) Non-Smad pathways in TGF-beta signaling. Cell Res 19:128–139

    PubMed  CAS  Google Scholar 

  141. Bellusci S, Henderson R, Winnier G, Oikawa T, Hogan BL (1996) Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. Development 122:1693–1702

    PubMed  CAS  Google Scholar 

  142. Southwood M, Jeffery TK, Yang X et al (2008) Regulation of bone morphogenetic protein signalling in human pulmonary vascular development. J Pathol 214:85–95

    PubMed  CAS  Google Scholar 

  143. Shi W, Chen H, Sun J et al (2004) Overexpression of Smurf1 negatively regulates mouse embryonic lung branching morphogenesis by specifically reducing Smad1 and Smad5 proteins. Am J Physiol Lung Cell Mol Physiol 286:L293–L300

    PubMed  CAS  Google Scholar 

  144. Long L, Crosby A, Yang X et al (2009) Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease. Circulation 119:566–576

    PubMed  CAS  Google Scholar 

  145. Morrell NW, Yang X, Upton PD et al (2001) Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation 104:790–795

    PubMed  CAS  Google Scholar 

  146. Zhang S, Fantozzi I, Tigno DD et al (2003) Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285:L740–L754

    PubMed  CAS  Google Scholar 

  147. Hansmann G, de Jesus Perez VA, Alastalo TP et al (2008) An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest 118:1846–1857

    Google Scholar 

  148. de Jesus Perez VA, Alastalo TP, Wu JC et al (2009) Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. J Cell Biol 184:83–99

    Google Scholar 

  149. Grantcharova E, Reusch HP, Beyermann M, Rosenthal W, Oksche A (2006) Endothelin A and endothelin B receptors differ in their ability to stimulate ERK1/2 activation. Exp Biol Med (Maywood) 231:757–760

    CAS  Google Scholar 

  150. Prenzel N, Zwick E, Daub H et al (1999) EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402:884–888

    PubMed  CAS  Google Scholar 

  151. Claing A, Laporte SA, Caron MG, Lefkowitz RJ (2002) Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and beta-arrestin proteins. Prog Neurobiol 66:61–79

    PubMed  CAS  Google Scholar 

  152. Bryja V, Gradl D, Schambony A, Arenas E, Schulte G (2007) Beta-arrestin is a necessary component of Wnt/beta-catenin ­signaling in vitro and in vivo. Proc Natl Acad Sci U S A 104:6690–6695

    PubMed  CAS  Google Scholar 

  153. Walsh CT, Radeff-Huang J, Matteo R et al (2008) Thrombin receptor and RhoA mediate cell proliferation through integrins and cysteine-rich protein 61. FASEB J 22:4011–4021

    PubMed  CAS  Google Scholar 

  154. Graves LM, Bornfeldt KE, Raines EW et al (1993) Protein kinase A antagonizes platelet-derived growth factor-induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells. Proc Natl Acad Sci U S A 90:10300–10304

    PubMed  CAS  Google Scholar 

  155. Azam MA, Yoshioka K, Ohkura S et al (2007) Ca2+-independent, inhibitory effects of cyclic adenosine 5’-monophosphate on Ca2+ regulation of phosphoinositide 3-kinase C2alpha, Rho, and myosin phosphatase in vascular smooth muscle. J Pharmacol Exp Ther 320:907–916

    PubMed  CAS  Google Scholar 

  156. Li P, Wang D, Lucas J et al (2008) Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res 102:185–192

    PubMed  CAS  Google Scholar 

  157. Long L, MacLean MR, Jeffery TK et al (2006) Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 98:818–827

    PubMed  CAS  Google Scholar 

  158. Liu F, Verin AD, Borbiev T, Garcia JG (2001) Role of cAMP-dependent protein kinase A activity in endothelial cell cytoskeleton rearrangement. Am J Physiol Lung Cell Mol Physiol 280:L1309–L1317

    PubMed  CAS  Google Scholar 

  159. El-Haroun H, Clarke DL, Deacon K et al (2008) IL-1beta, BK, and TGF-beta1 attenuate PGI2-mediated cAMP formation in human pulmonary artery smooth muscle cells by multiple mechanisms involving p38 MAP kinase and PKA. Am J Physiol Lung Cell Mol Physiol 294:L553–L562

    PubMed  CAS  Google Scholar 

  160. Morrell NW, Upton PD, Kotecha S et al (1999) Angiotensin II activates MAPK and stimulates growth of human pulmonary artery smooth muscle via AT1 receptors. Am J Physiol 277:L440–L448

    PubMed  CAS  Google Scholar 

  161. Taraseviciene-Stewart L, Scerbavicius R, Stewart JM et al (2005) Treatment of severe pulmonary hypertension: a bradykinin receptor 2 agonist B9972 causes reduction of pulmonary artery pressure and right ventricular hypertrophy. Peptides 26:1292–1300

    PubMed  CAS  Google Scholar 

  162. Smith AM, Elliot CM, Kiely DG, Channer KS (2006) The role of vasopressin in cardiorespiratory arrest and pulmonary hypertension. QJM 99:127–133

    PubMed  CAS  Google Scholar 

  163. Upton PD, Wharton J, Coppock H et al (2001) Adrenomedullin expression and growth inhibitory effects in distinct pulmonary artery smooth muscle cell subpopulations. Am J Respir Cell Mol Biol 24:170–178

    PubMed  CAS  Google Scholar 

  164. Petkov V, Mosgoeller W, Ziesche R et al (2003) Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 111:1339–1346

    PubMed  CAS  Google Scholar 

  165. Chattergoon NN, D’Souza FM, Deng W et al (2005) Antiproliferative effects of calcitonin gene-related peptide in aortic and pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 288:L202–L211

    PubMed  CAS  Google Scholar 

  166. Pedersen KE, Buckner CK, Meeker SN, Undem BJ (2000) Pharmacological examination of the neurokinin-1 receptor mediating relaxation of human intralobar pulmonary artery. J Pharmacol Exp Ther 292:319–325

    PubMed  CAS  Google Scholar 

  167. Ortiz JL, Labat C, Norel X, Gorenne I, Verley J, Brink C (1992) Histamine receptors on human isolated pulmonary arterial muscle preparations: effects of endothelial cell removal and nitric oxide inhibitors. J Pharmacol Exp Ther 260:762–767

    PubMed  CAS  Google Scholar 

  168. MacLean MR, Alexander D, Stirrat A et al (2000) Contractile responses to human urotensin-II in rat and human pulmonary arteries: effect of endothelial factors and chronic hypoxia in the rat. Br J Pharmacol 130:201–204

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (5K99HL091061-02), the Leukemia & Lymphoma Society (7332-06), and the Ellison Medical Foundation (AG-SS-1662-06).

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  1. Departments of Medicine and Pharmacology, University of California at San Diego, BSB 3073, 9500 Gilman Drive, La Jolla, CA, 92093-0636, USA

    Fiona Murray

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  1. Fiona Murray
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  2. Jason X.-J. Yuan
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  3. Paul A. Insel
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Editors and Affiliations

  1. Departments of Medicine, COMRB Rm. 3131 (MC 719), University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, 60612, Illinois, USA

    Jason X. -J. Yuan

  2. 310 Admin.Office Building (MC 672), University of Illinois at Chicago, 1737 W. Polk Street, Suite 310, Chicago, 60612, Illinois, USA

    Joe G.N. Garcia

  3. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0623, California, USA

    John B. West

  4. Dept. Pulmonary & Critical Care Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Charles A. Hales

  5. Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Stuart Rich

  6. Department of Medicine, University of Chicago School of Medicine, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Stephen L. Archer

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Murray, F., Yuan, J.XJ., Insel, P.A. (2011). Receptor-Mediated Signal Transduction and Cell Signaling. In: Yuan, JJ., Garcia, J., West, J., Hales, C., Rich, S., Archer, S. (eds) Textbook of Pulmonary Vascular Disease. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-87429-6_14

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