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Vascular control in humans: focus on the coronary microcirculation

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Abstract

Myocardial perfusion is regulated by a variety of factors that influence arteriolar vasomotor tone. An understanding of the physiological and pathophysiological factors that modulate coronary blood flow provides the basis for the judicious use of medications for the treatment of patients with coronary artery disease. Vasomotor properties of the coronary circulation vary among species. This review highlights the results of recent studies that examine the mechanisms by which the human coronary microcirculation is regulated in normal and disease states, focusing on diabetes. Multiple pathways responsible for myogenic constriction and flow-mediated dilation in human coronary arterioles are addressed. The important role of endothelium-derived hyperpolarizing factors, their interactions in mediating dilation, as well as speculation regarding the clinical significance are emphasized. Unique properties of coronary arterioles in human vs. other species are discussed.

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References

  1. Ahmed A, Waters CM, Leffler CW, Jaggar JH (2004) Ionic mechanisms mediating the myogenic response in newborn porcine cerebral arteries. Am J Physiol Heart Circ Physiol 287:H2061–H2069

    PubMed  CAS  Google Scholar 

  2. Ali MH, Schumacker PT (2002) Endothelial responses to mechanical stress: where is the mechanosensor? Crit Care Med 30:S198–S206

    PubMed  CAS  Google Scholar 

  3. Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry (Mosc) 70:200–214

    CAS  Google Scholar 

  4. Archer SL, Gragasin FS, Wu X, Wang S, McMurtry S, Kim DH, Platonov M, Koshal A, Hashimoto K, Campbell WB, Falck JR, Michelakis ED (2003) Endothelium-derived hyperpolarizing factor in human internal mammary artery is 11,12-epoxyeicosatrienoic acid and causes relaxation by activating smooth muscle BKCa channels. Circ 107:769–776

    CAS  Google Scholar 

  5. Aubin MC, Gendron ME, Lebel V, Thorin E, Tardif JC, Carrier M, Perrault LP (2007) Alterations in the endothelial G-protein coupled receptor pathway in epicardial arteries and subendocardial arterioles in compensated left ventricular hypertrophy. Basic Res Cardiol 102:144–153

    PubMed  CAS  Google Scholar 

  6. Bakker EN, Kerkhof CJ, Sipkema P (1999) Signal transduction in spontaneous myogenic tone in isolated arterioles from rat skeletal muscle. Cardiovasc Res 41:229–236

    PubMed  CAS  Google Scholar 

  7. Batenburg WW, Garrelds IM, van Kats JP, Saxena PR, Danser AH (2004) Mediators of bradykinin-induced vasorelaxation in human coronary microarteries. Hypertens 43:488–492

    CAS  Google Scholar 

  8. Bauersachs J, Popp RL, Hecker M, Sauer E, Fleming I, Busse R (1996) Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor. Circ 94:3341–3347

    CAS  Google Scholar 

  9. Baumgart D, Haude M, Gorge G, Liu F, Ge J, Grosse-Eggebrecht C, Erbel R, Heusch G (1999) Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circ 99:2090–2097

    CAS  Google Scholar 

  10. Beny JL, Pacicca C (1994) Bidirectional electrical communication between smooth muscle and endothelial cells in the pig coronary artery. Am J Physiol 266:H1465–H1472

    PubMed  CAS  Google Scholar 

  11. Bevan RD, Clementson A, Joyce E, Bevan JA (1993) Sympathetic denervation of resistance arteries increases contraction and decreases relaxation to flow. Am J Physiol 264:H490–H494

    PubMed  CAS  Google Scholar 

  12. Böse D, Leineweber K, Konorza T, Zahn A, Brocker-Preuss M, Mann K, Haude M, Erbel R, Heusch G (2007) Release of TNF-alpha during stent implantation into saphenous vein aortocoronary bypass grafts and its relation to plaque extrusion and restenosis. Am J Physiol Heart Circ Physiol 292:H2295–H2299

    PubMed  Google Scholar 

  13. Bouchard JF, Dumont EC, Lamontagne D (1999) Modification of vasodilator response in streptozotocin-induced diabetic rat. Can J Physiol Pharmacol 77:980–985

    PubMed  CAS  Google Scholar 

  14. Brayden JE, Nelson MT (1992) Regulation of arterial tone by activation of calcium-dependent potassium channels. Science 256:532–535

    PubMed  CAS  Google Scholar 

  15. Brodsky SV, Gealekman O, Chen J, Zhang F, Togashi N, Crabtree M, Gross SS, Nasjletti A, Goligorsky MS (2004) Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by ebselen. Circ Res 94:377–384

    PubMed  CAS  Google Scholar 

  16. Brown MR, Miller FJ, Jr., Li WG, Ellingson AN, Mozena JD, Chatterjee P, Engelhardt JF, Zwacka RM, Oberley LW, Fang X, Spector AA, Weintraub NL (1999) Overexpression of human catalase inhibits proliferation and promotes apoptosis in vascular smooth muscle cells. Circ Res 85:524–533

    PubMed  CAS  Google Scholar 

  17. Bubolz AH, Li H, Wu Q, Liu Y (2005) Enhanced oxidative stress impairs cAMP-mediated dilation by reducing Kv channel function in small coronary arteries of diabetic rats. Am J Physiol Heart Circ Physiol 289:H1873–H1880

    PubMed  CAS  Google Scholar 

  18. Bubolz AH, Wu Q, Larsen BT, Gutterman DD, Liu Y (2007) Ebselen reduces nitration and restores voltage-gated potassium channel function in small coronary arteries of diabetic rats. Am J Physiol Heart Circ Physiol 293:H2231–H2237

    PubMed  CAS  Google Scholar 

  19. Buus NH, Bottcher M, Bottker HE, Sorensen KE, Nielsen TT, Mulvany MJ (1999) Reduced vasodilator capacity in syndrome X related to structure and function of resistance arteries. Am J Cardiol 83:149–154

    PubMed  CAS  Google Scholar 

  20. Cadenas E, Boveris A, Ragan CI, Stoppani AO (1977) Production of superoxide radicals and hydrogen peroxide by NADH-ubiquinone reductase and ubiquinol-cytochrome c reductase from beef-heart mitochondria. Arch Biochem Biophys 180:248–257

    PubMed  CAS  Google Scholar 

  21. Camici PG, Crea F (2007) Coronary microvascular dysfunction. N Engl J Med 356:830–840

    PubMed  CAS  Google Scholar 

  22. Campbell WB, Gebremedhin D, Pratt PF, Harder DR (1996) Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res 78:415–423

    PubMed  CAS  Google Scholar 

  23. Capdevila JH, Falck JR, Estabrook RW (1992) Cytochrome P450 and the arachidonate cascade. FASEB J 6:731–736

    PubMed  CAS  Google Scholar 

  24. Ceriello A (2002) Nitrotyrosine: new findings as a marker of postprandial oxidative stress. Int J Clin Pract Suppl 51–58

  25. Ceriello A, Mercuri F, Quagliaro L, Assaloni R, Motz E, Tonutti L, Taboga C (2001) Detection of nitrotyrosine in the diabetic plasma: evidence of oxidative stress. Diabetologia 44:834–838

    PubMed  CAS  Google Scholar 

  26. Chien S (2007) Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. Am J Physiol Heart Circ Physiol 292:H1209–H1224

    PubMed  CAS  Google Scholar 

  27. Chilian WM (1991) Microvascular pressures and resistances in the left ventricular subepicardium and subendocardium. Circ Res 69:561–570

    PubMed  CAS  Google Scholar 

  28. Chilian WM, Kuo L, DeFily DV, Jones CJ, Davis MJ (1993) Endothelial regulation of coronary microvascular tone under physiological and pathophysiological conditions. Eur Heart J 14(suppl I):55–59

    PubMed  Google Scholar 

  29. Cipolla MJ, Gokina NI, Osol G (2002) Pressure-induced actin polymerization in vascular smooth muscle as a mechanism underlying myogenic behavior. FASEB J 16:72–76

    PubMed  CAS  Google Scholar 

  30. Clapp LH, Tinker A (1998) Potassium channels in the vasculature. Curr Opin Nephrol Hypertens 7:91–98

    PubMed  CAS  Google Scholar 

  31. Coats P, Johnston F, MacDonald J, McMurray JJ, Hillier C (2001) Endothelium-derived hyperpolarizing factor: identification and mechanisms of action in human subcutaneous resistance arteries. Circ 103:1702–1708

    CAS  Google Scholar 

  32. Cole WC, Clement-Chomienne O, Aiello EA (1996) Regulation of 4-aminopyridine-sensitive, delayed rectifier K+ channels in vascular smooth muscle by phosphorylation. Biochem Cell Biol 74:439–447

    Article  PubMed  CAS  Google Scholar 

  33. Cole WC, Plane F, Johnson R (2005) Role of Kv1 channels in control of arterial myogenic reactivity to intraluminal pressure. Circ Res 97:e1

    PubMed  CAS  Google Scholar 

  34. Coleman HA, Tare M, Parkington HC (2004) Endothelial potassium channels, endothelium-dependent hyperpolarization and the regulation of vascular tone in health and disease. Clin Exp Pharmacol Physiol 31:641–649

    PubMed  CAS  Google Scholar 

  35. Csiszar A, Ungvari Z, Edwards JG, Kaminski P, Wolin MS, Koller A, Kaley G (2002) Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res 90:1159–1166

    PubMed  CAS  Google Scholar 

  36. Davis MJ, Donovitz JA, Hood JD (1992) Stretch-activated single-channel and whole cell currents in vascular smooth muscle cells. Am J Physiol 262:C1083-C1088

    PubMed  CAS  Google Scholar 

  37. Davis MJ, Wu X, Nurkiewicz TR, Kawasaki J, Davis GE, Hill MA, Meininger GA (2001) Integrins and mechanotransduction of the vascular myogenic response. Am J Physiol Heart Circ Physiol 280:H1427–H1433

    PubMed  CAS  Google Scholar 

  38. Dernbach E, Randriamboavonjy V, Fleming I, Zeiher AM, Dimmeler S, Urbich C (2008) Impaired interaction of platelets with endothelial progenitor cells in patients with cardiovascular risk factors. Basic Res Cardiol 103:572–581

    PubMed  Google Scholar 

  39. Dessy C, Matsuda N, Hulvershorn J, Sougnez CL, Sellke FW, Morgan KG (2000) Evidence for involvement of the PKC-alpha isoform in myogenic contractions of the coronary microcirculation. Am J Physiol Heart Circ Physiol 279:H916–H923

    PubMed  CAS  Google Scholar 

  40. Deussen A, Heusch G, Thamer V (1985) Alpha–2 adrenoceptor-mediated coronary vasoconstriction persists after exhaustion of coronary dilator reserve. Eur J Pharmacol 115:147–153

    PubMed  CAS  Google Scholar 

  41. Earley S, Waldron BJ, Brayden JE (2004) Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ Res 95:922–929

    PubMed  CAS  Google Scholar 

  42. Egashira K, Suzuki S, Hirooka Y, Kai H, Sugimachi M, Imaizumi T, Takeshita A (1995) Impaired endothelium-dependent vasodilation of large epicardial and resistance coronary arteries in patients with essential hypertension: different responses to acteylcholine and substance p. Hypertens 25:201–206

    CAS  Google Scholar 

  43. Endo K, Abiru T, Machida H, Kasuya Y, Kamata K (1995) Endothelium-derived hyperpolarizing factor does not contribute to the decrease in endothelium-dependent relaxation in the aorta of streptozotocin-induced diabetic rats. Gen Pharmacol 26:149–153

    PubMed  CAS  Google Scholar 

  44. Feigl EO (1983) Coronary physiology. Physiol Rev 63:1–205

    PubMed  CAS  Google Scholar 

  45. Feliciano L, Henning RJ (1999) Coronary artery blood flow: physiologic and pathophysiologic regulation. Clin Cardiol 22:775–786

    Article  PubMed  CAS  Google Scholar 

  46. Fichtlscherer S, Dimmeler S, Breuer S, Busse R, Zeiher AM, Fleming I (2004) Inhibition of cytochrome P450 2C9 improves endothelium-dependent, nitric oxide-mediated vasodilatation in patients with coronary artery disease. Circ 109:178–183

    CAS  Google Scholar 

  47. Fisslthaler B, Popp R, Kiss L, Potente M, Harder DR, Fleming I, Busse R (1999) Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature 401:493–497

    PubMed  CAS  Google Scholar 

  48. Fitzgerald SM, Kemp-Harper BK, Parkington HC, Head GA, Evans RG (2007) Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor. Am J Physiol Regul Integr Comp Physiol 293:R707–R713

    PubMed  CAS  Google Scholar 

  49. Fleming I, Fisslthaler B, Michaelis UR, Kiss L, Popp R, Busse R (2001) The coronary endothelium-derived hyperpolarizing factor (EDHF) stimulates multiple signalling pathways and proliferation in vascular cells. Pflugers Arch 442:511–518

    PubMed  CAS  Google Scholar 

  50. Folgering JH, Sharif-Naeini R, Dedman A, Patel A, Delmas P, Honore E (2008) Molecular basis of the mammalian pressure-sensitive ion channels: Focus on vascular mechanotransduction. Prog Biophys Mol Biol 97:180–195

    PubMed  CAS  Google Scholar 

  51. Francis GS (2001) Pathophysiology of chronic heart failure Am J Med 110(suppl 7A):37S–46S

    PubMed  Google Scholar 

  52. Frisbee JC, Roman RJ, Falck JR, Krishna UM, Lombard JH (2001) 20-HETE contributes to myogenic activation of skeletal muscle resistance arteries in Brown Norway and Sprague-Dawley rats. Microcirculation 8:45–55

    PubMed  CAS  Google Scholar 

  53. Garcia SC, Pomblum V, Gams E, Langenbach MR, Schipke JD (2007) Independency of myocardial stunning of endothelial stunning? Basic Res Cardiol 102:359–367

    PubMed  CAS  Google Scholar 

  54. Gauthier KM, Deeter C, Krishna UM, Reddy YK, Bondlela M, Falck JR, Campbell WB (2002) 14,15-Epoxyeicosa–5(Z)-enoic acid: a selective epoxyeicosatrienoic acid antagonist that inhibits endothelium-dependent hyperpolarization and relaxation in coronary arteries. Circ Res 90:1028–1036

    PubMed  CAS  Google Scholar 

  55. Gebremedhin D, Harder DR, Pratt PF, Campbell WB (1998) Bioassay of an endothelium-derived hyperpolaraizing factor from bovine coronary arteries:role of a cytochrome P450 metabolite. J Vasc Res 35:274–284

    PubMed  CAS  Google Scholar 

  56. Gebremedhin D, Lange AR, Lowry TF, Taheri MR, Birks EK, Hudetz AG, Narayanan J, Falck JR, Okamoto H, Roman RJ, Nithipatikom K, Campbell WB, Harder DR (2000) Production of 20-HETE and its role in autoregulation of cerebral blood flow. Circ Res 87:60–65

    PubMed  CAS  Google Scholar 

  57. Gebremedhin D, Ma Y-H, Falck JR, Roman RJ, VanRollins M, Harder DR (1992) Mechanism of action of cerebral epoxyeicosatrienoic acids on cerebral arterial smooth muscle. Am J Physiol 263:H519–H525

    PubMed  CAS  Google Scholar 

  58. Godecke A, Decking UK, Ding Z, Hirchenhain J, Bidmon HJ, Godecke S, Schrader J (1998) Coronary hemodynamics in endothelial NO synthase knockout mice [In Process Citation]. Circ Res 82:186–194

    PubMed  CAS  Google Scholar 

  59. Gottlieb P, Folgering J, Maroto R, Raso A, Wood TG, Kurosky A, Bowman C, Bichet D, Patel A, Sachs F, Martinac B, Hamill OP, Honore E (2008) Revisiting TRPC1 and TRPC6 mechanosensitivity. Pflugers Arch 455:1097–1103

    PubMed  CAS  Google Scholar 

  60. Haitsma DB, Bac D, Raja N, Boomsma F, Verdouw PD, Duncker DJ (2001) Minimal impairment of myocardial blood flow responses to exercise in the remodeled left ventricle early after myocardial infarction, despite significant hemodynamic and neurohumoral alterations. Cardiovasc Res 52:417–428

    PubMed  CAS  Google Scholar 

  61. Harder DR, Campbell AB, Gebremedhin D, Pratt PF (1996) Bioassay of a cytochrome P450-dependent endothelial-derived hyperpolarizing factor from bovine coronary arteries. In: Vanhoutte PM (ed) Endothelial-derived hyperpolarizing factor. Harwood, Amsterdam, pp 73–80

    Google Scholar 

  62. Hattan N, Chilian WM, Park F, Rocic P (2007) Restoration of coronary collateral growth in the Zucker obese rat: impact of VEGF and ecSOD. Basic Res Cardiol 102:217–223

    PubMed  CAS  Google Scholar 

  63. Heintz A, Damm M, Brand M, Koch T, Deussen A (2008) Coronary flow regulation in mouse heart during hypercapnic acidosis: role of NO and its compensation during eNOS impairment. Cardiovasc Res 77:188–196

    PubMed  CAS  Google Scholar 

  64. Herrmann J, Haude M, Lerman A, Schulz R, Volbracht L, Ge J, Schmermund A, Wieneke H, von Birgelen C, Eggebrecht H, Baumgart D, Heusch G, Erbel R (2001) Abnormal coronary flow velocity reserve after coronary intervention is associated with cardiac marker elevation. Circ 103:2339–2345

    CAS  Google Scholar 

  65. Heusch G, Baumgart D, Camici P, Chilian W, Gregorini L, Hess O, Indolfi C, Rimoldi O (2000) alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circ 101:689–694

    CAS  Google Scholar 

  66. Heusch G, Deussen A (1983) The effects of cardiac sympathetic nerve stimulation on perfusion of stenotic coronary arteries in the dog. Circ Res 53:8–15

    PubMed  CAS  Google Scholar 

  67. Heusch G, Deussen A, Thamer V (1985) Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feed-back aggravation of myocardial ischemia. J Auton Nerv Syst 13:311–326

    PubMed  CAS  Google Scholar 

  68. Heusch G, Erbel R, Siffert W (2001) Genetic determinants of coronary vasomotor tone in humans. Am J Physiol Heart Circ Physiol 281:H1465-H1468

    PubMed  CAS  Google Scholar 

  69. Hirai N, Kawano H, Hirashima O, Motoyama T, Moriyama Y, Sakamoto T, Kugiyama K, Ogawa H, Nakao K, Yasue H (2000) Insulin resistance and endothelial dysfunction in smokers: effects of vitamin C. Am J Physiol Heart Circ Physiol 279:H1172-H1178

    PubMed  CAS  Google Scholar 

  70. Hsueh WA, Quinones MJ (2003) Role of endothelial dysfunction in insulin resistance. Am J Cardiol 92:10 J–17 J

    PubMed  CAS  Google Scholar 

  71. Hutcheson IR, Griffith TM (1996) Mechanotransduction through the endothelial cytoskeleton: mediation of flow- but not agonist-induced EDRF release. Br J Pharmacol 118:720–726

    PubMed  CAS  Google Scholar 

  72. Hutcheson IR, Griffith TM (1994) Heterogeneous populations of k+ channels mediate edrf release to flow but not agonists in rabbit aorta. Am J Physiol 266:H590-H596

    PubMed  CAS  Google Scholar 

  73. Inagaki N, Seino S (1998) ATP-sensitive potassium channels: structures, functions, and pathophysiology. Jpn J Physiol 48:397–412

    PubMed  CAS  Google Scholar 

  74. Jaggar JH, Wellman GC, Heppner TJ, Porter VA, Perez GJ, Gollasch M, Kleppisch T, Rubart M, Stevenson AS, Lederer WJ, Knot HJ, Bonev AD, Nelson MT (1998) Ca2+ channels, ryanodine receptors and Ca2+-activated K+ channels: a functional unit for regulating arterial tone. Acta Physiol Scand 164:577–587

    PubMed  CAS  Google Scholar 

  75. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Luscher TF (1995) Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circ 91:1314–1319

    CAS  Google Scholar 

  76. Kamata K, Miyata N, Kasuya Y (1989) Functional changes in potassium channels in aortas from rats with streptozotocin-induced diabetes. Eur J Pharmacol 166:319–323

    PubMed  CAS  Google Scholar 

  77. Kauser K, Rubanyi GM (1996) The NG-Nitro-l-Arginine insensitive endothelium-dependent relaxation of porcine coronary arteries is not mediated by a transferable relaxing substance. In: Vanhoutte PM (ed) Endothelium-derived hyperpolarizing factor. Harwood, Amsterdam, pp 33–39

    Google Scholar 

  78. Keller M, Lidington D, Vogel L, Peter BF, Sohn HY, Pagano PJ, Pitson S, Spiegel S, Pohl U, Bolz SS (2006) Sphingosine kinase functionally links elevated transmural pressure and increased reactive oxygen species formation in resistance arteries. FASEB J 20:702–704

    PubMed  CAS  Google Scholar 

  79. Kersten JR, Brooks LA, Dellsperger KC (1995) Impaired microvascular response to graded coronary occlusion in diabetic and hyperglycemic dogs. Am J Physiol 268:H1667–H1674

    PubMed  CAS  Google Scholar 

  80. Khan TA, Bianchi C, Ruel M, Voisine P, Li J, Liddicoat JR, Sellke FW (2003) Mitogen-activated protein kinase inhibition and cardioplegia-cardiopulmonary bypass reduce coronary myogenic tone. Circ 108 Suppl 1:II348–II353

    Google Scholar 

  81. Knot HJ, Standen NB, Nelson MT (1998) Ryanodine receptors regulate arterial diameter and wall Ca2+ in cerebral arteries of rat via Ca2+-dependent K+ channels. J Physiol 508 (Pt 1):211–221

    PubMed  CAS  Google Scholar 

  82. Koller A (2002) Signaling pathways of mechanotransduction in arteriolar endothelium and smooth muscle cells in hypertension. Microcirculation 9:277–294

    PubMed  CAS  Google Scholar 

  83. Koller A, Huang A, Sun D, Kaley G (1995) Exercise training augments flow-dependent dilation in rat skeletal muscle arterioles: role of endothelial nitric oxide and prostaglandins. Circ Res 76:544–550

    PubMed  CAS  Google Scholar 

  84. Koller A, Kaley G (1990) Prostaglandins mediate arteriolar dilation to increased blood flow velocity in skeletal muscle microcirculation. Circ Res 67:529–534

    PubMed  CAS  Google Scholar 

  85. Koshida R, Rocic P, Saito S, Kiyooka T, Zhang C, Chilian WM (2005) Role of focal adhesion kinase in flow-induced dilation of coronary arterioles. Arterioscler Thromb Vasc Biol 25:2548–2553

    PubMed  CAS  Google Scholar 

  86. Kuo L, Chilian WM, Davis MJ (1990) Coronary arteriolar myogenic response is independent of endothelium. Circ Res 66:860–866

    PubMed  CAS  Google Scholar 

  87. Kuo L, Chilian WM, Davis MJ (1991) Interaction of pressure- and flow-induced responses in porcine coronary resistance vessels. Am J Physiol 261:H1706-H1715

    PubMed  CAS  Google Scholar 

  88. Larsen BT, Campbell WB, Gutterman DD (2007) Beyond vasodilatation: non-vasomotor roles of epoxyeicosatrienoic acids in the cardiovascular system. Trends Pharmacol Sci 28:32–38

    PubMed  CAS  Google Scholar 

  89. Larsen BT, Gutterman DD, Sato A, Toyama K, Campbell WB, Zeldin DC, Manthati VL, Falck JR, Miura H (2008) Hydrogen peroxide inhibits cytochrome p450 epoxygenases: interaction between two endothelium-derived hyperpolarizing factors. Circ Res 102:59–67

    PubMed  CAS  Google Scholar 

  90. Lauer T, Heiss C, Balzer J, Kehmeier E, Mangold S, Leyendecker T, Rottler J, Meyer C, Merx MW, Kelm M, Rassaf T (2008) Age-dependent endothelial dysfunction is associated with failure to increase plasma nitrite in response to exercise. Basic Res Cardiol 103:291–297

    PubMed  CAS  Google Scholar 

  91. Learmont JG, Cockell AP, Knock GA, Poston L (1996) Myogenic and flow-mediated responses in isolated mesenteric small arteries from pregnant and nonpregnant rats. Am J Obstet Gynecol 174:1631–1636

    PubMed  CAS  Google Scholar 

  92. Lefroy DC, Wharton J, Crake T, Knock GA, Rutherford RA, Suzuki T, Morgan K, Polak JM, Poole-Wilson PA (1996) Regional changes in angiotensin II receptor density after experimental myocardial infarction. J Mol Cell Cardiol 28:429–440

    PubMed  CAS  Google Scholar 

  93. Leineweber K, Böse D, Vogelsang M, Haude M, Erbel R, Heusch G (2006) Intense vasoconstriction in response to aspirate from stented saphenous vein aortocoronary bypass grafts. J Am Coll Cardiol 47:981–986

    PubMed  Google Scholar 

  94. Li H, Chai Q, Gutterman DD, Liu Y (2003) Elevated glucose impairs cAMP-mediated dilation by reducing Kv channel activity in rat small coronary smooth muscle cells. Am J Physiol Heart Circ Physiol 285: H1213–H1219

    PubMed  CAS  Google Scholar 

  95. Lieberman EH, Gerhard MD, Uehata A, Selwyn AP, Ganz P, Yeung AC, Creager MA (1996) Flow-induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease. Am J Cardiol 78:1210–1214

    PubMed  CAS  Google Scholar 

  96. Liu S, Beckman JS, Ku DD (1994) Peroxynitrite, a product of superoxide and nitric oxide, produces coronary vasorelaxation in dogs. J Pharmacol Exp Ther 268:1114–1121

    PubMed  CAS  Google Scholar 

  97. Liu Y, Li H, Bubolz AH, Zhang DX, Gutterman DD (2008) Endothelial cytoskeletal elements are critical for flow-mediated dilation in human coronary arterioles. Med Biol Eng Comput 46:469–478

    PubMed  Google Scholar 

  98. Liu Y, Terata K, Chai Q, Li H, Kleinman LH, Gutterman DD (2002) Peroxynitrite inhibits Ca2+-activated K+ channel activity in smooth muscle of human coronary arterioles. Circ Res 91:1070–1076

    PubMed  CAS  Google Scholar 

  99. Liu Y, Terata K, Rusch NJ, Gutterman DD (2001) High glucose impairs voltage-gated K+ channel current in rat small coronary arteries. Circ Res 89:146–152

    PubMed  CAS  Google Scholar 

  100. Liu Y, Zhao H, Li H, Kalyanaraman B, Nicolosi AC, Gutterman DD (2003) Mitochondrial sources of H2O2 generation play a key role in flow-mediated dilation in human coronary resistance arteries. Circ Res 93:573–580

    PubMed  CAS  Google Scholar 

  101. Liu ZG, Ge ZD, He GW (2000) Difference in hyperpolarizing factor-mediated hyperpolarization and nitric oxide release between human internal mammary artery and saphenous vein. Circ 102:III296–III301

    CAS  Google Scholar 

  102. Maas M, Wang R, Paddock C, Kotamraju S, Kalyanaraman B, Newman PJ, Newman DK (2003) Reactive oxygen species induce reversible PECAM-1 tyrosine phosphorylation and SHP-2 binding. Am J Physiol Heart Circ Physiol 285:H2336–H2344

    PubMed  CAS  Google Scholar 

  103. Maier KG, Roman RJ (2001) Cytochrome P450 metabolites of arachidonic acid in the control of renal function. Curr Opin Nephrol Hypertens 10:81–87

    PubMed  CAS  Google Scholar 

  104. Matoba T, Shimokawa H (2003) Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J Pharmacol Sci 92:1–6

    PubMed  CAS  Google Scholar 

  105. 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

    PubMed  CAS  Google Scholar 

  106. Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, Kanaide H, Takeshita A (2000) Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest 106:1521–1530

    PubMed  CAS  Google Scholar 

  107. Mayhan WG (1994) Effect of diabetes mellitus on response of the basilar artery to activation of ATP-sensitive potassium channels. Brain Res 636:35–39

    PubMed  CAS  Google Scholar 

  108. Mayhan WG, Faraci FM (1993) Responses of cerebral arterioles in diabetic rats to activation of ATP- sensitive potassium channels. Am J Physiol 265:H152–H157

    PubMed  CAS  Google Scholar 

  109. Meininger GA, Davis MJ (1992) Cellular mechanisms involved in the vascular myogenic response. Am J Physiol 263:H647–H659

    PubMed  CAS  Google Scholar 

  110. Meirhaeghe A, Bauters C, Helbecque N, Hamon M, McFadden E, Lablanche JM, Bertrand M, Amouyel P (2001) The human G-protein beta3 subunit C825T polymorphism is associated with coronary artery vasoconstriction. Eur Heart J 22:845–848

    PubMed  CAS  Google Scholar 

  111. Meredith IT, Yeung AC, Weidinger FF, Anderson TJ, Uehata A, Ryan TJ, Jr., Selwyn AP, Ganz P (1993) Role of impaired endothelium-dependent vasodilation in ishcemic manifestations of coronary artery disease. Circ 87 (suppl.V):V-56–V-66

    Google Scholar 

  112. Miller FJ, Dellsperger KC, Gutterman DD (1997) Myogenic vasoconstriciton of human coronary arterioles. Am J Physiol 273:H257–H264

    PubMed  CAS  Google Scholar 

  113. Miura H, Bosnjak JJ, Ning G, Saito T, Miura M, Gutterman DD (2003) Role for hydrogen peroxide in flow-induced dilation of human coronary arterioles. Circ Res 92:e31–e40

    PubMed  CAS  Google Scholar 

  114. Miura H, Liu Y, Gutterman DD (1999) Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization. Circ 99:3132–3138

    CAS  Google Scholar 

  115. Miura H, Wachtel RE, Liu Y, Loberiza FR, Jr., Saito T, Miura M, Gutterman DD (2001) Flow-induced dilation of human coronary arterioles: important role of Ca2+-activated K+ channels. Circ 103:1992–1998

    CAS  Google Scholar 

  116. Miura H, Wachtel RE, Loberiza FR, Jr., Saito T, Miura M, Nicolosi AC, Gutterman DD (2003) Diabetes mellitus impairs vasodilation to hypoxia in human coronary arterioles: reduced activity of ATP-sensitive potassium channels. Circ Res 92:151–158

    PubMed  CAS  Google Scholar 

  117. Murakami H, Urabe K, Nishimura M (1998) Inappropriate microvascular constriction produced transient ST-segment elevation in patients with syndrome X. J Am Coll Cardiol 32:1287–1294

    PubMed  CAS  Google Scholar 

  118. Naber CK, Baumgart D, Altmann C, Siffert W, Erbel R, Heusch G (2001) eNOS 894T allele and coronary blood flow at rest and during adenosine-induced hyperemia. Am J Physiol Heart Circ Physiol 281:H1908–H1912

    PubMed  CAS  Google Scholar 

  119. Nahser PJJ, Brown RE, Oskarsson H, Winniford MD, Rossen JD (1995) Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circ 91:635–640

    Google Scholar 

  120. Nishio E, Watanabe Y (1997) The involvement of reactive oxygen species and arachidonic acid in alpha 1-adrenoceptor-induced smooth muscle cell proliferation and migration. Br J Pharmacol 121:665–670

    PubMed  CAS  Google Scholar 

  121. Nitenberg A, Valensi P, Sachs R, Dali M, Aptecar E, Attali JR (1993) Impairment of coronary vascular reserve and ACh-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function. Diabetes 42:1017–1025

    PubMed  CAS  Google Scholar 

  122. Nithipatikom K, DiCamelli RF, Kohler S, Gumina RJ, Falck JR, Campbell WB, Gross GJ (2001) Determination of cytochrome P450 metabolites of arachidonic acid in coronary venous plasma during ischemia and reperfusion in dogs. Anal Biochem 292:115–124

    PubMed  CAS  Google Scholar 

  123. Node K, Huo Y, Ruan X, Yang B, Spiecker M, Ley K, Zeldin DC, Liao JK (1999) Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285:1276–1279

    PubMed  CAS  Google Scholar 

  124. Nowicki PT, Flavahan S, Hassanain H, Mitra S, Holland S, Goldschmidt-Clermont PJ, Flavahan NA (2001) Redox signaling of the arteriolar myogenic response. Circ Res 89:114–116

    PubMed  CAS  Google Scholar 

  125. Nwasokwa ON (1995) Coronary artery bypass graft disease. Ann Intern Med 123:528–545

    PubMed  CAS  Google Scholar 

  126. Pitkänen O-P, Raitakari OT, Niinikoski H, Nuutila P, IIda H, Voipio-Pulkki L-M, Härkönen R, Wegelius U, Rönnemaa T, Viikari J, Knuuti J (1996) Coronary flow reserve is impaired in young men with familial hypercholesterolemia. J Am Coll Cardiol 28:1705–1711

    PubMed  Google Scholar 

  127. Possati G, Gaudino M, Prati F, Alessandrini F, Trani C, Glieca F, Mazzari MA, Luciani N, Schiavoni G (2003) Long-term results of the radial artery used for myocardial revascularization. Circ 108:1350–1354

    Google Scholar 

  128. Quyyumi AA (2003) Prognostic value of endothelial function. Am J Cardiol 91:19H–24H

    PubMed  CAS  Google Scholar 

  129. Roman RJ (2002) P–450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 82:131–185

    PubMed  CAS  Google Scholar 

  130. Sato A, Miura H, Liu Y, Somberg LB, Otterson MF, Demeure MJ, Schulte WJ, Eberhardt LM, Loberiza FR, Sakuma I, Gutterman DD (2002) Effect of gender on endothelium-dependent dilation to bradykinin in human adipose microvessels. Am J Physiol Heart Circ Physiol 283:H845–H852

    PubMed  CAS  Google Scholar 

  131. Sharif-Naeini R, Dedman A, Folgering JH, Duprat F, Patel A, Nilius B, Honore E (2008) TRP channels and mechanosensory transduction: insights into the arterial myogenic response. Pflugers Arch 456:529–540

    PubMed  CAS  Google Scholar 

  132. Shimokawa H, Morikawa K (2005) Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J Mol Cell Cardiol 39:725–732

    PubMed  CAS  Google Scholar 

  133. Shiode N, Morishima N, Nakayama K, Yamagata T, Matsuura H, Kajiyama G (1996) Flow-mediated vasodilation of human epicardial coronary arteries: effect of inhibition of nitric oxide synthesis. J Am Coll Cardiol 27:304–310

    PubMed  CAS  Google Scholar 

  134. Slish DF, Welsh DG, Brayden JE (2002) Diacylglycerol and protein kinase C activate cation channels involved in myogenic tone. Am J Physiol Heart Circ Physiol 283: H2196–H2201

    PubMed  CAS  Google Scholar 

  135. Spiecker M, Liao JK (2005) Vascular protective effects of cytochrome p450 epoxygenase-derived eicosanoids. Arch Biochem Biophys 433:413–420

    PubMed  CAS  Google Scholar 

  136. Sun D, Huang A, Sharma S, Koller A, Kaley G (2001) Endothelial microtubule disruption blocks flow-dependent dilation of arterioles. Am J Physiol Heart Circ Physiol 280:H2087–H2093

    PubMed  CAS  Google Scholar 

  137. Sun H, Mohri M, Shimokawa H, Usui M, Urakami L, Takeshita A (2002) Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina. J Am Coll Cardiol 39:847–851

    PubMed  Google Scholar 

  138. Sun J, Sui X, Bradbury JA, Zeldin DC, Conte MS, Liao JK (2002) Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids. Circ Res 90:1020–1027

    PubMed  CAS  Google Scholar 

  139. Tanner FC, van der LB, Shaw S, Greutert H, Bachschmid MM, Berrozpe M, Rozenberg I, Blau N, Siebenmann R, Schmidli J, Meyer P, Luscher TF (2007) Inactivity of nitric oxide synthase gene in the atherosclerotic human carotid artery. Basic Res Cardiol 102:308–317

    PubMed  CAS  Google Scholar 

  140. Terashvili M, Pratt PF, Gebremedhin D, Narayanan J, Harder DR (2006) Reactive oxygen species cerebral autoregulation in health and disease. Pediatr Clin North Am 53:1029–1037

    PubMed  Google Scholar 

  141. Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, Tsikas D, Ertl G, Bauersachs J (2007) Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes 56:666–674

    PubMed  CAS  Google Scholar 

  142. Tokube K, Kiyosue T, Arita M (1996) Openings of cardiac KATP channel by oxygen free radicals produced by xanthine oxidase reaction. Am J Physiol 271:H478–H489

    PubMed  CAS  Google Scholar 

  143. Treasure CB, Klein JL, Vita JA, Manoukian SV, Renwick GH, Selwyn AP, Ganz P, Alexander RW (1993) Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels. Circ 87:86–93

    CAS  Google Scholar 

  144. Ueeda M, Silvia SK, Olsson RA (1992) Nitric oxide modulates coronary autoregulation in the guinea pig. Circ Res 70:1296–1303

    PubMed  CAS  Google Scholar 

  145. van Kats JP, Duncker DJ, Haitsma DB, Schuijt MP, Niebuur R, Stubenitsky R, Boomsma F, Schalekamp MA, Verdouw PD, Danser AH (2000) Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent cardiac remodeling in pigs after myocardial infarction: role of tissue angiotensin II. Circ 102:1556–1563

    Google Scholar 

  146. Veerareddy S, Cooke CL, Baker PN, Davidge ST (2004) Gender differences in myogenic tone in superoxide dismutase knockout mouse: animal model of oxidative stress. Am J Physiol Heart Circ Physiol 287:H40–H45

    PubMed  CAS  Google Scholar 

  147. Virag L, Szabo E, Gergely P, Szabo C (2003) Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol Lett 140–141:113–124

    PubMed  Google Scholar 

  148. Wang MH, Zhang F, Marji J, Zand BA, Nasjletti A, Laniado-Schwartzman M (2001) CYP4A1 antisense oligonucleotide reduces mesenteric vascular reactivity and blood pressure in SHR. Am J Physiol Regul Integr Comp Physiol 280:R255–R261

    PubMed  CAS  Google Scholar 

  149. Wang SY, Friedman M, Franklin A, Sellke FW (1995) Myogenic reactivity of coronary resistance arteries after cardiopulmonary bypass and hyperkalemic cardioplegia. Circ 92: x1590–1596

    Google Scholar 

  150. Wei K, Kaul S (2004) The coronary microcirculation in health and disease. Cardiol Clin 22:221–231

    PubMed  Google Scholar 

  151. Welsh DG, Morielli AD, Nelson MT, Brayden JE (2002) Transient receptor potential channels regulate myogenic tone of resistance arteries. Circ Res 90:248–250

    PubMed  CAS  Google Scholar 

  152. Welsh DG, Nelson MT, Eckman DM, Brayden JE (2000) Swelling-activated cation channels mediate depolarization of rat cerebrovascular smooth muscle by hyposmolarity and intravascular pressure. J Physiol 527 Pt 1:139–148

    PubMed  CAS  Google Scholar 

  153. Wesselman JP, Schubert R, VanBavel ED, Nilsson H, Mulvany MJ (1997) KCa-channel blockade prevents sustained pressure-induced depolarization in rat mesenteric small arteries. Am J Physiol 272:H2241–H2249

    PubMed  CAS  Google Scholar 

  154. Wesselman JP, Spaan JA, van der Meulen ET, VanBavel E (2001) Role of protein kinase C in myogenic calcium-contraction coupling of rat cannulated mesenteric small arteries. Clin Exp Pharmacol Physiol 28:848–855

    PubMed  CAS  Google Scholar 

  155. Yokoyama I, Ohtake T, Momomura S, Nishikawa J, Sasaki Y, Omata M (1996) Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis. Circ 94:3232–3238

    CAS  Google Scholar 

  156. Zou MH, Shi C, Cohen RA (2002) High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H2 receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes 51:198–203

    PubMed  CAS  Google Scholar 

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Acknowledgments

This review was supported by funding from NIH-NHLBI (R01HL067968 and R01HL080704), an American Heart Association Fellowship, and the VA Merit Review Program.

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Authors and Affiliations

  1. National Center for Research Resources, National Institutes of Health, Bethesda, MD, USA

    Yanping Liu

  2. Dept. of Medicine and Cardiovascular Center, The Medical College of Wisconsin, The Veterans Administration Medical Center, Milwaukee, WI, USA

    David D. Gutterman MD

  3. Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA

    David D. Gutterman MD

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  1. Yanping Liu
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Correspondence to David D. Gutterman MD.

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Returned for 1. Revision: 4 September 2008 1. Revision received: 7 October 2008

Returned for 2. Revision: 27 October 2008 2. Revision received: 10 November 2008

Returned for 3. Revision: 2 December 2008 3. Revision received: 15 December 2008

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Liu, Y., Gutterman, D.D. Vascular control in humans: focus on the coronary microcirculation. Basic Res Cardiol 104, 211–227 (2009). https://doi.org/10.1007/s00395-009-0775-y

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