Abstract
Coronary vascular endothelial cells control vascular tone by modulating the local concentration of circulating vasoactive substances (e.g. adenine nucleotides, biogenic amines and bradykinin) and by synthesising and releasing the vasoactive autacoids nitric oxide (NO) and prostacyclin (PGI2). The fluid shear stress exerted by the streaming blood is the physiologically most important stimulus for a continuous endothelial NO production, which counteracts neuro- and myogenic constriction. This shear stress-dependent NO release represents a highly effective local system for maintaining adequate blood flow to the myocardial tissue. At the transcriptional level endothelium-derived NO modulates the regulation of a number of genes (e.g. monocyte chemoattractant protein-1, P-selectin and vascular cell adhesion molecule-1) most probably by direct and/or indirect interaction with transcription factors.
In addition to NO and PGI2, the coronary vascular endothelium is also able to release a factor which causes hyperpolarisation of the underlying smooth muscle. This so-called endothelium-derived hyperpolarising factor (EDHF) displays the characteristics of a cytochrome P450-derived arachidonic acid metabolite. However, since NO is able to attenuate production of this factor, EDHF may contribute to the regulation of vascular tone essentially in situations associated with an apparent dysfunction of the endothelium.
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References
Busse R, Fleming I: Regulation and functional consequences of endothelial nitric oxide formation. Ann Med 27: 331–340, 1995
Martin W, White DG, Henderson AH: Endothelium-derived relaxing factor and atriopeptin 11 elevate cyclic GMP levels in pig aortic endothelial cells. Br J Pharmacol 93: 229–239, 1988
Walter U: Physiological role of cGMP and cAMP-dependent protein kinase in the cardiovascular system. Rev Physiol Biochem Pharmacol 113: 41–88, 1989
Schrör K: Prostaglandins, other eicosanoids and endothelial cells. Basic Res Cardiol 80: 502–514, 1985
Hong SL, Deykin D: Activation of phospholipases A2 and C in pig aortic endothelial cells synthetizing prostacyclin. J Biol Chem 257: 7151–7154, 1982
Lückhoff A, Pohl U, Mülsch A, Busse R: Differential role of extraand intracellular calcium in the release of EDRF and prostacyclin from cultured endothelial cells. Br J Pharmacol 95: 189–196, 1988
Garland CJ, Plane F, Kemp BK, Cocks TM: Endothelium-dependent hyperpolarization: a role in the control of vascular tone. Trends Pharmacol Sci 16: 23–30, 1995
Chen G, Yamamoto Y, Miwa K, Suzuki H: Hyperpolarization of arterial smooth muscle by endothelial Immoral substances. Am J Physiol 260: H1888-H1892, 1991
Kauser K, Rubanyi GM: Bradykinin-induced, nitro-L-arginine-insensitive endothelium-dependent relaxation of porcine coronary artery is not mediated by bioassayable substances. J Cardiovasc Pharmacol 20 (Suppl. 12): S101-S104, 1992
Hecker M, Bara AT, Bauersachs J, Busse R: Characterization of endothelium-derived hyperpolarizing factor as a cytochrome P450derived arachidonic acid metabolite in mammals. J Physiol 481: 407–414,1994
Popp R, Bauersachs J, Sauer E, Fleming I, Hecker M, Busse R: P-450 pathway and NO-indepedent relaxations. Endothelium 1996, (in press)
Fulton D, McGiff JC, Quilley J: Role of K+ channels in the vasodilator response to bradykinin in the rat heart. Br J Pharmacol 113: 954–958, 1994
Bauersachs J, Hecker M, Busse R: Display of the characteristics of endothelium-derived hyperpolarizing factor by a cytochrome P450derived arachidonic acid metabolite in the coronary microcirculation. Br J Pharmacol 113: 1548–1553, 1994
Fulton D, Mahboubi K, McGiff JC, Quilley J: Cytochrome P450dependent effects of bradykinin in the rat heart. Br J Pharmacol 114: 99–102,1995
Rosolowsky M, Campbell WB: Role of PGI2 and epoxyeicosatrienic acids in relaxation of bovine coronary arteries to arachidonic acid. Am J Physiol 264: H327-H335, 1993
Hu S, Kim HS: Activation of K+ channel in vascular smooth muscles by cytochrome P450 metabolites of arachidonic acids. Eur J Pharmacol 230: 215–221, 1993
Assreuy J, Cunha FQ, Liew FY, Moncada S: Feedback inhibition of nitric oxide synthase activity by nitric oxide. Br J Pharmacol 108: 833–837, 1993
Griscavage JM, Fukuto JM, Komori Y, Ignarro LJ: Nitric oxide inhibits neuronal nitric oxide synthase by interacting with the heme prosthetic group. J Biol Chem 269: 21644–21649, 1994
Benzing T, Winter I, Busse R: Feedback inhibition by NO of the Cal2+-dependent autacoid formation in human endothelial cells is mediated by cyclic GMP. Pflügers Arch 420 (Suppl.l): 467 1992 (Abstract)
Shin WS, Sasaki T, Kato M, Hara K, Seko A, Yang W-D, Shimamoto N, Sugimoto T, Toyo-oka T: Autocrine and paracrine effects of endothelium-derived relaxing factor on intracellular Ca z. of endothelial cells and vascular smooth muscle cells. J Biol Chem 267: 20377–20382, 1992
Lang D, Lewis MJ: Endothelium-derived relaxing factor inhibits the formation of inositol trisphosphate by rabbit aorta. J Physiol 411: 45–52, 1989
Ormandy GC, Jope RS: Sodium nitroprusside and guanosine 3′,5′-monophosphate (cyclic GMP) inhibit stimulated phosphoinositide hydrolysis in rat cerebral cortical slices. Neurosci Lett 100: 287–291, 1989
Gallone A, White A, Willmott N, Turner M, Potter BVL, Watson SP: cGMP mobilizes intracellular Cat. in sea urchin eggs by stimulating ADP-ribose synthesis. Nature 365: 456–159, 1993
Graier WF, Groschner K, Schmidt K, Kukovetz WR: Increases in endothelial cyclic AMP levels amplify agonist-induced formation of endothelium-derived relaxing factor (EDRF). Biochem J 288: 345–349,1992
Kilpatrick EV, Cocks TM: Evidence for differential roles of nitric oxide (NO) and hyperpolarization in endothelium-dependent relaxation of pig isolated coronary artery. Br J Pharmacol 112: 557–565, 1994
Busse R, Mülsch A: Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett 265: 133–136,1990
Fleming I, Hecker M, Busse R: Intracellular alkalinization induced by bradykinin sustains activation ofthe constitutive nitric oxide synthase in endothelial cells. Circ Res 74: 1220–1226, 1994
Fleming I, Fisslthaler B, Busse R: Calcium signaling in endothelial cells involves activation of tyrosine kinases and leads to activation of MAP kinase. Circ Res 76: 522–529, 1995
Fleming I, Fisslthaler B, Busse R: Interdependency of calcium signalling and protein tyrosine phosphorylation in human endothelial cells. J Biol Chem 1996 (in press)
Fleming I, Bara A, Busse R: Calcium signalling and autacoid production in endothelial cells are modulated by changes in tyrosine kinase and phosphatase activity. J Vasc Res 1995
Caselli A, Camici G, Manao G, Moneti G, Pazzagli L, Cappugi G, Ramponi G: Nitric oxide causes inactivation of the low molecular weight phosphotyrosine protein phosphatase. J Biol Chem 269: 24878–24882, 1994
Peranovich TMS, Da Silva AM, Fries DM, Stern A, Monteiro HP: Nitric oxide stimulates tyrosine phosphorylation in murine fibroblasts in the absence and presence of epidermal growth factor. Biochem J 305: 613–619, 1995
Blumer KJ, Johnson GL: Diversity in function and regulation of MAP kinase pathways. Trends Biochem Sci 19: 236–240, 1994
Nishida K, Harrison DG, Navas JP, Fisher AA, Dockery SP, Uematsu M, Nerem RM, Alexander RW, Murphy TJ: Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest 90: 2092–2096, 1992
Davies PF: Flow-mediated endothelial mechanotransduction. Physiol Rev 75: 519–560, 1995
Morita T, Kurihara H, Maemura K, Yoshizumi M, Yazaki Y: Disruption of cytoskeletal structures mediates shear stress-induced endothelin-1 gene expression in cultured porcine aortic endothelial cells. J Clin Invest 92: 1706–1712, 1993
Kuchan MJ, Frangos JA: Role of calcium and calmodulin in flowinduced nitric oxide production in endothelial cells. Am J Physiol 266: C628-C636, 1994
Ayajiki K, Kindermann M, Hecker M, Fleming 1, Busse R: Intracellular pH and tyrosine phosphorylation but not calcium determine shear stress-induced nitric oxide production in native endothelial cells. 1996 Circ Res (in press)
Ziegelstein RC, Cheng L, Capogrossi MC: Flow-dependent cytosolic acidification of vascular endothelial cells. Science 258: 656–659, 1992
Schlaepfer DD, Hanks SK, Hunter T, van der Geer P: Integrin-mediated signal transduction linked to Ras pathway binding to focal adhesion kinase. Nature 372: 786–791, 1994
Davenpeck KL, Gauthier TW, Lefer AM: Inhibition of endothelialderived nitric oxide promotes P-selectin expression and actions in the rat microcirculation. Gastroenterology 107: 1050–1058, 1994
Rösen P, Schwippert P, Kaufman B, Tschope D: Expression of adhesion molecules on the surface of activated platelets is diminished by PGI2 analogues and an NO (EDRF)-donor: a comparison between platelets of healthy subjects and diabetic subjects. Platelets 11: 42–57, 1994
Gauthier TW, Davenpeck KL, Lefer AM: Nitric oxide attenuates leukocyte and endothelial interaction via P-selectin in splanchnic ischemia-reperfusion. Am J Physiol 267: G562-G568, 1994
Zeiher AM, Fisslthaler B, Schray-Utz B, Busse R: Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells. Circ Res 76: 980–986, 1995
Shyy Y-J, Hsieh H-J, Usami S, Chien S: Fluid shear stress induces a biphasic response of human monocyte chemotactic protein 1 gene expression in vascular endothelium. Proc Natl Acad Sci USA 91: 4678–4682, 1994
De Caterina R, Libby P, Peng H-B, Thannickal VJ, Rajavashisth TB, Gimbrone MA, Jr., Shin WS, Liao JK: Nitric oxide decreases cytokineinduced endothelial activation. J Clin Invest 96: 60–68, 1995
Peng H-B, Libby P, Liao JK: Induction and stabilization of IKBa by nitric oxide mediates inhbition of NFKB. J Biol Chem 270: 14214–14219, 1995
Meyer M, Schreck R, Baeuerle PA: H 202 and antioxidants have opposite effects on activation of NF-κB and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J 12: 2005–2015, 1993
Tabuchi A, Sano K, Oh E, Tsuchiya T, Tsuda M: Modulation of AP-1 activity by nitric oxide (NO) in vitro: NO-mediated modulation of AP-1. FEBS Lett 351: 123–127, 1994
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Fleming, I., Bauersachs, J. & Busse, R. Paracrine functions of the coronary vascular endothelium. Mol Cell Biochem 157, 137–145 (1996). https://doi.org/10.1007/BF00227892
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DOI: https://doi.org/10.1007/BF00227892