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Endothelium-Derived Factors

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Biology of Vascular Smooth Muscle: Vasoconstriction and Dilatation

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Abstract

The endothelium-dependent regulation of vascular tone is predominantly by four major players: nitric oxide (NO), prostaglandin I2 (PGI2), endothelium-derived hyperpolarizing factor (EDHF), and endothelin-1 (ET-1). The former three are vasodilators, while ET-1 is a potent vasoconstrictor. NO and PGI2 exert their effects primarily by activating, respectively, cGMP–cGMP-dependent protein kinase (PKG) and cAMP–cAMP-dependent pathways, which result in decreased Ca2+ influx, suppressed Ca2+ release from the sarcoplasmic reticulum, reduced sensitivity of myofilament to Ca2+, and consequently vasodilatation. Unlike NO and PGI2, the identity of EDHF differs depending on vessel sizes and types as well as species. The better known two EDHFs are epoxyeicosatrienoic acids (EETs) and H2O2. All EDHFs cause vasodilatation mainly by activation of K+ channels, leading to membrane hyperpolarization and decreased Ca2+ influx. Among these vasodilators, NO is the dominant player, PGI2 often has a complementary role, and EDHFs are more important in resistant arteries where NO is less crucial. The vasodilatory effects of these agents are counteracted by various vasoconstrictors in particular ET-1, which exerts its effect by stimulating Ca2+ influx, promoting Ca2+ release from the sarcoplasmic reticulum, and enhancing Ca2+ sensitivity of myofilament. ET-1 has delicate and complicated interactions with endothelium-derived NO as well as other vasodilators. The balance between the constrictor actions and dilator actions is essential for vascular hemostasis.

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References

  • Aird WC (2007) Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 100:158–173

    Article  CAS  PubMed  Google Scholar 

  • Alexander SPH, Mathie A, Peters JA (2011) Guide to Receptors and Channels (GRAC), 5th edn. Br J Pharmacol 164(Suppl. 1):S1–S324

    Article  CAS  PubMed  Google Scholar 

  • Bagnall AJ, Kelland NF, Gulliver-Sloan F, Davenport AP, Gray GA, Yanagisawa M, Webb DJ, Kotelevtsev YV (2006) Deletion of endothelial cell endothelin b receptors does not affect blood pressure or sensitivity to salt. Hypertension 48:286–293

    Article  CAS  PubMed  Google Scholar 

  • Balligand JL, Feron O, Dessy C (2009) eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol Rev 89:481–534

    Article  CAS  PubMed  Google Scholar 

  • Billecke SS, Bender AT, Kanelakis KC, Murphy PJ, Lowe ER, Kamada Y, Pratt WB, Osawa Y (2002) hsp90 is required for heme binding and activation of apo-neuronal nitric-oxide synthase: geldanamycin-mediated oxidant generation is unrelated to any action of hsp90. J Biol Chem 277:20504–20509

    Article  CAS  PubMed  Google Scholar 

  • Blandin V, Vigne P, Breittmayer JP, Frelin C (2000) Allosteric inhibition of endothelin ETA receptors by 3, 5-dibromosalicylic acid. Mol Pharmacol 58:1461–1469

    CAS  PubMed  Google Scholar 

  • Bouallegue A, Daou GB, Srivastava AK (2007) Nitric oxide attenuates endothelin-1-induced activation of erk1/2, pkb, and PYK2 in vascular smooth muscle cells by a cGMP-dependent pathway. Am J Physiol Heart Circ Physiol 293:H2072–H2079

    Article  CAS  PubMed  Google Scholar 

  • Boulanger C, Luscher TF (1990) Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 85:587–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bremnes T, Paasche JD, Mehlum A, Sandberg C, Bremnes B, Attramadal H (2000) Regulation and intracellular trafficking pathways of the endothelin receptors. J Biol Chem 275:17596–17604

    Article  CAS  PubMed  Google Scholar 

  • Brunner F, Stessel H, Kukovetz WR (1995) Novel guanylyl cyclase inhibitor, odq reveals role of nitric oxide, but not of cyclic gmp in endothelin-1 secretion. FEBS Lett 376:262–266

    Article  CAS  PubMed  Google Scholar 

  • Burgoyne JR, Oka S, Ale-Agha N, Eaton P (2013) Hydrogen peroxide sensing and signaling by protein kinases in the cardiovascular system. Antioxid Redox Signal 18:1042–1052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell WB, Fleming I (2010) Epoxyeicosatrienoic acids and endothelium-dependent responses. Pflugers Arch 459:881–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao S, Yao J, Shah V (2003) The proline-rich domain of dynamin-2 is responsible for dynamin-dependent in vitro potentiation of endothelial nitric-oxide synthase activity via selective effects on reductase domain function. J Biol Chem 278:5894–5901

    Article  CAS  PubMed  Google Scholar 

  • Caplin B, Leiper J (2012) Endogenous nitric oxide synthase inhibitors in the biology of disease: markers, mediators, and regulators? Arterioscler Thromb Vasc Biol 32:1343–1353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chatterjee S, Cao S, Peterson TE, Simari RD, Shah V (2003) Inhibition of GTP-dependent vesicle trafficking impairs internalization of plasmalemmal eNOS and cellular nitric oxide production. J Cell Sci 116:3645–3655

    Article  CAS  PubMed  Google Scholar 

  • Chen K, Popel AS (2006) Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells. Free Radic Biol Med 41:668–680

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Xiao H, Rizzo AN, Zhang W, Mai Y, Ye M (2014) Endothelial nitric oxide synthase dimerization is regulated by heat shock protein 90 rather than by phosphorylation. PLoS One 9:e105479

    Article  PubMed  PubMed Central  Google Scholar 

  • Daff S (2010) NO synthase: structures and mechanisms. Nitric Oxide 23:1–11

    Article  CAS  PubMed  Google Scholar 

  • Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ (2016) Endothelin. Pharmacol Rev 68:357–418

    Article  PubMed  PubMed Central  Google Scholar 

  • Dupuis J, Stewart DJ, Cernacek P, Gosselin G (1996) Human pulmonary circulation is an important site for both clearance and production of endothelin-1. Circulation 94:1578–1584

    Article  CAS  PubMed  Google Scholar 

  • Durieux AC, Prudhon B, Guicheney P, Bitoun M (2010) Dynamin 2 and human diseases. J Mol Med (Berl) 88:339–350

    Article  Google Scholar 

  • Edwards G, FĂ©lĂ©tou M, Weston AH (2010) Endothelium-derived hyperpolarising factors and associated pathways: a synopsis. Pflugers Arch 459:863–879

    Article  CAS  PubMed  Google Scholar 

  • FĂ©lĂ©tou M, Huang Y, Vanhoutte PM (2011) Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol 164:894–912

    Article  PubMed  PubMed Central  Google Scholar 

  • Fitzpatrick FA, Soberman R (2001) Regulated formation of eicosanoids. J Clin Invest 107:1347–1351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flavahan NA (2007) Balancing prostanoid activity in the human vascular system. Trends Pharmacol Sci 28:106–110

    Article  CAS  PubMed  Google Scholar 

  • Fleming I (2010) Molecular mechanisms underlying the activation of eNOS. Pflugers Arch 459:793–806

    Article  CAS  PubMed  Google Scholar 

  • Förstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:829–837. 837a–837d

    Article  PubMed  Google Scholar 

  • Förstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H (1994) Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension 23:1121–1131

    Article  PubMed  Google Scholar 

  • Frömel T, Fleming I (2015) Whatever happened to the epoxyeicosatrienoic acid-like endothelium-derived hyperpolarizing factor? The identification of novel classes of lipid mediators and their role in vascular homeostasis. Antioxid Redox Signal 22:1273–1292

    Article  PubMed  Google Scholar 

  • Gambone LM, Murray PA, Flavahan NA (1997) Synergistic interaction between endothelium-derived NO and prostacyclin in pulmonary artery: potential role for KATP channels. Br J Pharmacol 121:271–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gandhi CR, Kang Y, De Wolf A, Madariaga J, Aggarwal S, Scott V, Fung J (1996) Altered endothelin homeostasis in patients undergoing liver transplantation. Liver Transpl Surg 2:362–369

    Article  CAS  PubMed  Google Scholar 

  • Gao Y, Portugal AD, Negash S, Zhou W, Longo LD, Usha Raj J (2007) Role of rho kinases in pkg-mediated relaxation of pulmonary arteries of fetal lambs exposed to chronic high altitude hypoxia. Am J Phys Lung Cell Mol Phys 292:L678–L684

    CAS  Google Scholar 

  • Gao Y, Portugal AD, Liu J, Negash S, Zhou W, Tian J, Xiang R, Longo LD, Raj JU (2008) Preservation of cgmp-induced relaxation of pulmonary veins of fetal lambs exposed to chronic high altitude hypoxia: role of PKG and Rho kinase. Am J Phys Lung Cell Mol Phys 295:L889–L896

    CAS  Google Scholar 

  • Gao Y, Chen T, Raj JU (2016) Endothelial and smooth muscle cell interactions in the pathobiology of pulmonary hypertension. Am J Respir Cell Mol Biol 54:451–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • GarcĂ­a-Cardeña G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, Sessa WC (1998) Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 392:821–824

    Article  PubMed  Google Scholar 

  • Ghosh A, Chawla-Sarkar M, Stuehr DJ (2011) Hsp90 interacts with inducible NO synthase client protein in its heme-free state and then drives heme insertion by an ATP-dependent process. FASEB J 25:2049–2060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gluais P, Lonchampt M, Morrow JD, Vanhoutte PM, Feletou M (2005) Molecular mechanisms underlying the activation of eNOS. Br J Pharmacol 146:834–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guignabert C, Dorfmuller P (2013) Pathology and pathobiology of pulmonary hypertension. Semin Respir Crit Care Med 34:551–559

    Article  PubMed  Google Scholar 

  • Haas TL, Duling BR (1997) Morphology favors an endothelial cell pathway for longitudinal conduction within arterioles. Microvasc Res 53:113–120

    Article  CAS  PubMed  Google Scholar 

  • Henrion D, Dechaux E, Dowell FJ, Maclour J, Samuel JL, LĂ©vy BI, Michel JB (1997) Alteration of flow-induced dilatation in mesenteric resistance arteries of L-NAME treated rats and its partial association with induction of cyclo-oxygenase-2. Br J Pharmacol 121:83–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ho JJ, Man HS, Marsden PA (2012) Nitric oxide signaling in hypoxia. J Mol Med (Berl) 90:217–231

    Article  CAS  Google Scholar 

  • Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377:239–242

    Article  CAS  PubMed  Google Scholar 

  • Kar S, Kavdia M (2011) Modeling of biopterin-dependent pathways of eNOS for nitric oxide and superoxide production. Free Radic Biol Med 51:1411–1427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klatt P, Pfeiffer S, List BM, Lehner D, Glatter O, Bächinger HP, Werner ER, Schmidt K, Mayer B (1996) Characterization of heme-deficient neuronal nitric-oxide synthase reveals a role for heme in subunit dimerization and binding of the amino acid substrate and tetrahydrobiopterin. J Biol Chem 271:7336–7342

    Article  CAS  PubMed  Google Scholar 

  • List BM, Klosch B, Volker C, Gorren AC, Sessa WC, Werner ER, Kukovetz WR, Schmidt K, Mayer B (1997) Characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled NADPH oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerization. Biochem J 323:159–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Bubolz AH, Mendoza S, Zhang DX, Gutterman DD (2011) H2O2 is the transferrable factor mediating flow-induced dilation in human coronary arterioles. Circ Res 108:566–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lowenstein CJ, Morrell CN, Yamakuchi M (2005) Regulation of weibel-palade body exocytosis. Trends Cardiovasc Med 15:302–308

    Article  CAS  PubMed  Google Scholar 

  • Majed BH, Khalil RA (2012) Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn. Pharmacol Rev 64:540–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maron BA, Zhang YY, White K, Chan SY, Handy DE, Mahoney CE, Loscalzo J, Leopold JA (2012) Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension. Circulation 126:963–974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matoba T, Shimokawa H, Morikawa K, Kubota H, Kunihiro I, Urakami-Harasawa L, Mukai Y, Hirakawa Y, Akaike T, Takeshita A (2003) Electron spin resonance detection of hydrogen peroxide as an endothelium-derived hyperpolarizing factor in porcine coronary microvessels. Arterioscler Thromb Vasc Biol 23:1224–1230

    Article  CAS  PubMed  Google Scholar 

  • Mitsutomi N, Akashi C, Odagiri J, Matsumura Y (1999) Effects of endogenous and exogenous nitric oxide on endothelin-1 production in cultured vascular endothelial cells. Eur J Pharmacol 364:65–73

    Article  CAS  PubMed  Google Scholar 

  • Moncada S (2006) Adventures in vascular biology: a tale of two mediators. Philos Trans R Soc Lond Ser B Biol Sci 361:735–759

    Article  CAS  Google Scholar 

  • 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 (1997) Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 388:678–682

    Article  CAS  PubMed  Google Scholar 

  • Oksche A, Boese G, Horstmeyer A, Furkert J, Beyermann M, Bienert M, Rosenthal W (2000) Late endosomal/lysosomal targeting and lack of recycling of the ligand-occupied endothelin B receptor. Mol Pharmacol 57:1104–1113

    CAS  PubMed  Google Scholar 

  • Pace NJ, Weerapana E (2014) Zinc-binding cysteines: diverse functions and structural motifs. Biomolecules 4:419–434

    Article  PubMed  PubMed Central  Google Scholar 

  • Prysyazhna O, Rudyk O, Eaton P (2012) Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension. Nat Med 18:286–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puybasset L, BĂ©a ML, Ghaleh B, Giudicelli JF, Berdeaux A (1996) Coronary and systemic hemodynamic effects of sustained inhibition of nitric oxide synthesis in conscious dogs. Evidence for cross talk between nitric oxide and cyclooxygenase in coronary vessels. Circ Res 79:343–357

    Article  CAS  PubMed  Google Scholar 

  • Qian J, Fulton D (2013) Post-translational regulation of endothelial nitric oxide synthase in vascular endothelium. Front Physiol 4:347

    Article  PubMed  PubMed Central  Google Scholar 

  • Ramadoss J, Pastore MB, Magness RR (2013) Endothelial caveolar subcellular domain regulation of endothelial nitric oxide synthase. Clin Exp Pharmacol Physiol 40:753–764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson MA, Baumgardner JE, Otto CM (2011) Oxygen-dependent regulation of nitric oxide production by inducible nitric oxide synthase. Free Radic Biol Med 51:1952–1965

    Article  CAS  PubMed  Google Scholar 

  • Saito Y, Kazuwa N, Shirakami G, Mukoyama M, Arai H, Hosoda K, Suga S, Ogawa Y, Imura H (1991) Endothelin in patients with chronic renal failure. J Cardiovasc Pharmacol 17(Suppl 7):S437–S439

    Article  CAS  PubMed  Google Scholar 

  • Sandoval YH, Atef ME, Levesque LO, Li Y, Anand-Srivastava MB (2014) Endothelin-1 signaling in vascular physiology and pathophysiology. Curr Vasc Pharmacol 12:202–214

    Article  CAS  PubMed  Google Scholar 

  • Sandow SL, Senadheera S, Bertrand PP, Murphy TV, Tare M (2012) Myoendothelial contacts, gap junctions, and microdomains: anatomical links to function? Microcirculation 19:403–415

    Article  CAS  PubMed  Google Scholar 

  • Sauvageau S, Thorin E, Villeneuve L, Dupuis J (2009) Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: role of etb-receptor expression levels. Pulm Pharmacol Ther 22:311–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Searles CD (2006) Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression. Am J Phys Cell Physiol 291:C803–C816

    Article  CAS  Google Scholar 

  • Shimokawa H (2010) Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pflugers Arch 459:915–922

    Article  CAS  PubMed  Google Scholar 

  • Shimokawa H, Godo S (2016) Diverse functions of endothelial NO synthases system: NO and EDH. J Cardiovasc Pharmacol 67:361–366

    Article  CAS  PubMed  Google Scholar 

  • Smith AP, Demoncheaux EA, Higenbottam TW (2002) Nitric oxide gas decreases endothelin-1 mrna in cultured pulmonary artery endothelial cells. Nitric Oxide 6:153–159

    Article  CAS  PubMed  Google Scholar 

  • Strachan FE, Spratt JC, Wilkinson IB, Johnston NR, Gray GA, Webb DJ (1999) Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men. Hypertension 33:581–585

    Article  CAS  PubMed  Google Scholar 

  • Stuehr DJ, Santolini J, Wang ZQ, Wei CC, Adak S (2004) Update on mechanism and catalytic regulation in the NO synthases. J Biol Chem 279:36167–36170

    Article  CAS  PubMed  Google Scholar 

  • Tang EH, Vanhoutte PM (2008) Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension. Physiol Genomics 32:409–418

    Article  CAS  PubMed  Google Scholar 

  • Tang EH, Vanhoutte PM (2009) Prostanoids and reactive oxygen species: team players in endothelium-dependent contractions. Pharmacol Ther 122:140–149

    Article  CAS  PubMed  Google Scholar 

  • Thorin E, Webb DJ (2010) Endothelium-derived endothelin-1. Pflugers Arch 459:951–958

    Article  CAS  PubMed  Google Scholar 

  • Vanhoutte PM, Shimokawa H, Feletou M, Tang EH (2017) Endothelial dysfunction and vascular disease – a 30th anniversary update. Acta Physiol (Oxford) 219:22–96

    Article  CAS  Google Scholar 

  • Wagner OF, Christ G, Wojta J, Vierhapper H, Parzer S, Nowotny PJ, Schneider B, Waldhausl W, Binder BR (1992) Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 267:16066–16068

    CAS  PubMed  Google Scholar 

  • Williams SP, Dorn GW 2nd, Rapoport RM (1994) Prostaglandin I2 mediates contraction and relaxation of vascular smooth muscle. Am J Phys 267:H796–H803

    CAS  Google Scholar 

  • Zellers TM, YQ W, McCormick J, Vanhoutte PM (2000) Prostacyclin-induced relaxations of small porcine pulmonary arteries are enhanced by the basal release of endothelium-derived nitric oxide through an effect on cyclic GMP-inhibited cyclic AMP phosphodiesterase. Acta Pharmacol Sin 21:131–138

    CAS  PubMed  Google Scholar 

  • Zhang DX, Borbouse L, Gebremedhin D, Mendoza SA, Zinkevich NS, Li R, Gutterman DD (2012) H2O2-induced dilation in human coronary arterioles: role of protein kinase G dimerization and large-conductance Ca2+-activated K+ channel activation. Circ Res 110:471–480

    Article  CAS  PubMed  Google Scholar 

  • Zou MH (2007) Peroxynitrite and protein tyrosine nitration of prostacyclin synthase. Prostaglandins Other Lipid Mediat 82:119–127

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China

    Yuansheng Gao

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Gao, Y. (2017). Endothelium-Derived Factors. In: Biology of Vascular Smooth Muscle: Vasoconstriction and Dilatation. Springer, Singapore. https://doi.org/10.1007/978-981-10-4810-4_8

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