The Human Microcirculation: Regulation of Flow and beyond

Circulation Research

Volumn 118, Issue 1, 2016, Pages 157-172

  Gutterman, David D ^a   Chabowski, Dawid S ^a   Kadlec, Andrew O ^a   Durand, Matthew J ^a   Freed, Julie K ^a   Ait Aissa, Karima ^a   Beyer, Andreas M ^a  

^a MEDICAL COLLEGE OF WISCONSIN   (United States)

Author keywords

microcirculation; muscle, smooth, vascular; nitric oxide; oxidative stress; vasodilation

Indexed keywords

ACETYLCHOLINE; ADENOSINE; ARACHIDONIC ACID; BRADYKININ; LARGE CONDUCTANCE CALCIUM ACTIVATED POTASSIUM CHANNEL; NITRIC OXIDE; REACTIVE OXYGEN METABOLITE; VOLTAGE GATED POTASSIUM CHANNEL;

ARTERIOLE; BLOOD VESSEL REACTIVITY; BLOOD VESSEL TONE; CARDIOVASCULAR DISEASE; CELL PROLIFERATION; CORONARY ARTERY BLOOD FLOW; HEART MUSCLE FIBROSIS; HOMEOSTASIS; HUMAN; HYPOXIA; INFLAMMATION; MICROCIRCULATION; NONHUMAN; OXYGEN CONSUMPTION; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; THROMBOSIS; TISSUE PERFUSION; VASCULAR ENDOTHELIUM; VASODILATATION; ANIMAL; CARDIOVASCULAR DISEASES; CIRCULATION; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; BLOOD CIRCULATION; CARDIOVASCULAR DISEASES; ENDOTHELIUM, VASCULAR; HUMANS; MICROCIRCULATION; VASODILATION;

EID: 84954534623     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.115.305364     Document Type: Review

References (217)

1. Bassingthwaighte JB, King RB, Roger SA. Fractal nature of regional myocardial blood flow heterogeneity. Circ Res. 1989;65:578-590.
2. Avakian A, Kalina RE, Sage EH, Rambhia AH, Elliott KE, Chuang EL, Clark JI, Hwang JN, Parsons-Wingerter P. Fractal analysis of region-based vascular change in the normal and non-proliferative diabetic retina. Curr Eye Res. 2002;24:274-280.
3. Nagaoka T, Yoshida A. Relationship between retinal fractal dimensions and retinal circulation in patients with type 2 diabetes mellitus. Curr Eye Res. 2013;38:1148-1152. doi: 10.3109/02713683.2013.805232.
4. Lanza GA, Crea F. Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation. 2010;121:2317-2325. doi: 10.1161/CIRCULATIONAHA.109.900191.
5. Brush JE Jr, Cannon RO 3rd, Schenke WH, Bonow RO, Leon MB, Maron BJ, Epstein SE. Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med. 1988;319:1302-1307. doi: 10.1056/NEJM198811173192002.
6. Cannon RO III, Epstein SE. "Microvascular angina" as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol. 1988;61:1338-1343.
7. Cannon RO III, Camici PG, Epstein SE. Pathophysiological dilemma of syndrome x. Circulation. 1992;85:883-892.
8. den Uil CA, Lagrand WK, van der Ent M, Jewbali LS, Cheng JM, Spronk PE, Simoons ML. Impaired microcirculation predicts poor outcome of patients with acute myocardial infarction complicated by cardiogenic shock. Eur Heart J. 2010;31:3032-3039. doi: 10.1093/eurheartj/ehq324.
9. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002;106:653-658.
10. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med. 2003;349:1027-1035. doi: 10.1056/NEJMoa025050.
11. Mitchell GF, Parise H, Vita JA, Larson MG, Warner E, Keaney JF Jr, Keyes MJ, Levy D, Vasan RS, Benjamin EJ. Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study. Hypertension. 2004;44:134-139. doi: 10.1161/01.HYP.0000137305.77635.68.
12. van de Hoef TP, van Lavieren MA, Damman P, Delewi R, Piek MA, Chamuleau SA, Voskuil M, Henriques JP, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. Circ Cardiovasc Interv. 2014;7:301-311. doi: 10.1161/CIRCINTERVENTIONS.113.001049.
13. Taqueti VR, Everett BM, Murthy VL, Gaber M, Foster CR, Hainer J, Blankstein R, Dorbala S, Di Carli MF. Interaction of impaired coronary flow reserve and cardiomyocyte injury on adverse cardiovascular outcomes in patients without overt coronary artery disease. Circulation. 2015;131:528-535. doi: 10.1161/CIRCULATIONAHA.114.009716.
14. Murthy VL, Naya M, Taqueti VR, Foster CR, Gaber M, Hainer J, Dorbala S, Blankstein R, Rimoldi O, Camici PG, Di Carli MF. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation. 2014;129:2518-2527. doi: 10.1161/CIRCULATIONAHA.113.008507.
15. van Kranenburg M, Magro M, Thiele H, et al. Prognostic value of microvascular obstruction and infarct size, as measured by CMR in STEMI patients. JACC Cardiovasc Imaging. 2014;7:930-939. doi: 10.1016/j. jcmg.2014.05.010.
16. Rizzoni D, Porteri E, De Ciuceis C, Boari GE, Zani F, Miclini M, Paiardi S, Tiberio GA, Giulini SM, Muiesan ML, Castellano M, Rosei EA. Lack of prognostic role of endothelial dysfunction in subcutaneous small resistance arteries of hypertensive patients. J Hypertens. 2006;24:867-873. doi: 10.1097/01.hjh.0000222756.76982.53.
17. Nahser PJ Jr, Brown RE, Oskarsson H, Winniford MD, Rossen JD. Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation. 1995;91:635-640.
18. Di Carli MF, Janisse J, Grunberger G, Ager J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J Am Coll Cardiol. 2003;41:1387-1393.
19. Chan W, Stub D, Clark DJ, Ajani AE, Andrianopoulos N, Brennan AL, New G, Black A, Shaw JA, Reid CM, Dart AM, Duffy SJ; Melbourne Interventional Group Investigators. Usefulness of transient and persistent no reflow to predict adverse clinical outcomes following percutaneous coronary intervention. Am J Cardiol. 2012;109:478-485. doi: 10.1016/j. amjcard.2011.09.037.
20. Fabregat-Andrés Ó, Cubillos A, Ferrando-Beltrán M, Bochard-Villanueva B, Estornell-Erill J, Fácila L, Ridocci-Soriano F, Morell S. Mean platelet volume is associated with infarct size and microvascular obstruction estimated by cardiac magnetic resonance in ST segment elevation myocardial infarction. Blood Coagul Fibrinolysis. 2013;24:424-427. doi: 10.1097/MBC.0b013e32835d9bca.
21. Kloner RA, Ganote CE, Jennings RB. The "no-reflow" phenomenon after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496-1508. doi: 10.1172/JCI107898.
22. Robbers LF, Eerenberg ES, Teunissen PF, Jansen MF, Hollander MR, Horrevoets AJ, Knaapen P, Nijveldt R, Heymans MW, Levi MM, van Rossum AC, Niessen HW, Marcu CB, Beek AM, van Royen N. Magnetic resonance imaging-defined areas of microvascular obstruction after acute myocardial infarction represent microvascular destruction and haemorrhage. Eur Heart J. 2013;34:2346-2353. doi: 10.1093/eurheartj/eht100.
23. Carrick D, Oldroyd KG, McEntegart M, et al. A randomized trial of deferred stenting versus immediate stenting to prevent no-or slow-reflow in acute ST-segment elevation myocardial infarction (DEFER-STEMI). J Am Coll Cardiol. 2014;63:2088-2098. doi: 10.1016/j.jacc.2014.02.530.
24. Zeiher AM, Drexler H, Wollschläger H, Just H. Endothelial dysfunction of the coronary microvasculature is associated with coronary blood flow regulation in patients with early atherosclerosis. Circulation. 1991;84:1984-1992.
25. Gilligan DM, Guetta V, Panza JA, Garciá CE, Quyyumi AA, Cannon RO 3rd. Selective loss of microvascular endothelial function in human hypercholesterolemia. Circulation. 1994;90:35-41.
26. Rubinshtein R, Yang EH, Rihal CS, Prasad A, Lennon RJ, Best PJ, Lerman LO, Lerman A. Coronary microcirculatory vasodilator function in relation to risk factors among patients without obstructive coronary disease and low to intermediate Framingham score. Eur Heart J. 2010;31:936-942. doi: 10.1093/eurheartj/ehp459.
27. Zeiher AM, Krause T, Schächinger V, Minners J, Moser E. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation. 1995;91:2345-2352.
28. Reis SE, Holubkov R, Conrad Smith AJ, Kelsey SF, Sharaf BL, Reichek N, Rogers WJ, Merz CN, Sopko G, Pepine CJ; WISE Investigators. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J. 2001;141:735-741.
29. von Mering GO, Arant CB, Wessel TR, McGorray SP, Bairey Merz CN, Sharaf BL, Smith KM, Olson MB, Johnson BD, Sopko G, Handberg E, Pepine CJ, Kerensky RA; National Heart, Lung, and Blood Institute. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation. 2004;109:722-725. doi: 10.1161/01.CIR.0000115525.92645.16.
30. Pepine CJ, Anderson RD, Sharaf BL, Reis SE, Smith KM, Handberg EM, Johnson BD, Sopko G, Bairey Merz CN. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study. J Am Coll Cardiol. 2010;55:2825-2832. doi: 10.1016/j.jacc.2010.01.054.
31. Scalia R. The microcirculation in adipose tissue inflammation. Rev Endocr Metab Disord. 2013;14:69-76. doi: 10.1007/s11154-013-9236-x.
32. Patt BT, Jarjoura D, Haddad DN, Sen CK, Roy S, Flavahan NA, Khayat RN. Endothelial dysfunction in the microcirculation of patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2010;182:1540-1545. doi: 10.1164/rccm.201002-0162OC.
33. Rigo F, Sicari R, Citro R, Ossena G, Buja P, Picano E. Diffuse, marked, reversible impairment in coronary microcirculation in stress cardiomyopathy: a Doppler transthoracic echo study. Ann Med. 2009;41:462-470. doi: 10.1080/07853890903022793.
34. Treasure CB, Vita JA, Cox DA, Fish RD, Gordon JB, Mudge GH, Colucci WS, Sutton MG, Selwyn AP, Alexander RW. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation. 1990;81:772-779.
35. Laguens R, Alvarez P, Vigliano C, Cabeza Meckert P, Favaloro L, Diez M, Favaloro R. Coronary microcirculation remodeling in patients with idiopathic dilated cardiomyopathy. Cardiology. 2011;119:191-196. doi: 10.1159/000331440.
36. Prasad A, Higano ST, Al Suwaidi J, Holmes DR Jr, Mathew V, Pumper G, Lennon RJ, Lerman A. Abnormal coronary microvascular endothelial function in humans with asymptomatic left ventricular dysfunction. Am Heart J. 2003;146:549-554. doi: 10.1016/S0002-8703(03)00364-8.
37. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62:263-271. doi: 10.1016/j.jacc.2013.02.092.
38. Deban L, Correale C, Vetrano S, Malesci A, Danese S. Multiple pathogenic roles of microvasculature in inflammatory bowel disease: a Jack of all trades. Am J Pathol. 2008;172:1457-1466. doi: 10.2353/ajpath.2008.070593.
39. Hatoum OA, Gauthier KM, Binion DG, Miura H, Telford G, Otterson MF, Campbell WB, Gutterman DD. Novel mechanism of vasodilation in inflammatory bowel disease. Arterioscler Thromb Vasc Biol. 2005;25:2355-2361. doi: 10.1161/01.ATV.0000184757.50141.8d.
40. Moises HW, Wollschläger D, Binder H. Functional genomics indicate that schizophrenia may be an adult vascular-ischemic disorder. Transl Psychiatry. 2015;5:e616. doi: 10.1038/tp.2015.103.
41. Migrino RQ, Hari P, Gutterman DD, Bright M, Truran S, Schlundt B, Phillips SA. Systemic and microvascular oxidative stress induced by light chain amyloidosis. Int J Cardiol. 2010;145:67-68. doi: 10.1016/j. ijcard.2009.04.044.
42. Miura H, Toyama K, Pratt PF, Gutterman DD. Cigarette smoking impairs Na+-K+-ATPase activity in the human coronary microcirculation. Am J Physiol Heart Circ Physiol. 2011;300:H109-H117. doi: 10.1152/ajpheart.00237.2010.
43. Holowatz LA. Human cutaneous microvascular ageing: potential insights into underlying physiological mechanisms of endothelial function and dysfunction. J Physiol. 2008;586:3301. doi: 10.1113/jphysiol.2008.157594.
44. Wright SA, O'Prey FM, Rea DJ, Plumb RD, Gamble AJ, Leahey WJ, Devine AB, McGivern RC, Johnston DG, Finch MB, Bell AL, McVeigh GE. Microcirculatory hemodynamics and endothelial dysfunction in systemic lupus erythematosus. Arterioscler Thromb Vasc Biol. 2006;26:2281-2287. doi: 10.1161/01.ATV.0000238351.82900.7f.
45. Thijssen DH, Green DJ, Hopman MT. Blood vessel remodeling and physical inactivity in humans. J Appl Physiol (1985). 2011;111:1836-1845. doi: 10.1152/japplphysiol.00394.2011.
46. Feher A, Chen SY, Bagi Z, Arora V. Prevention and treatment of noreflow phenomenon by targeting the coronary microcirculation. Rev Cardiovasc Med. 2014;15:38-51.
47. Feng J, Liu Y, Clements RT, Sodha NR, Khabbaz KR, Senthilnathan V, Nishimura KK, Alper SL, Sellke FW. Calcium-activated potassium channels contribute to human coronary microvascular dysfunction after cardioplegic arrest. Circulation. 2008;118:S46-S51. doi: 10.1161/CIRCULATIONAHA.107.755827.
48. Mohri M, Shimokawa H, Hirakawa Y, Masumoto A, Takeshita A. Rhokinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. J Am Coll Cardiol. 2003;41:15-19.
49. Naraoka M, Matsuda N, Shimamura N, Asano K, Ohkuma H. The role of arterioles and the microcirculation in the development of vasospasm after aneurysmal SAH. Biomed Res Int. 2014;2014:253746. doi: 10.1155/2014/253746.
50. Medhora M, Daniels J, Mundey K, Fisslthaler B, Busse R, Jacobs ER, Harder DR. Epoxygenase-driven angiogenesis in human lung microvascular endothelial cells. Am J Physiol Heart Circ Physiol. 2003;284:H215-H224. doi: 10.1152/ajpheart.01118.2001.
51. Datla SR, Peshavariya H, Dusting GJ, Mahadev K, Goldstein BJ, Jiang F. Important role of Nox4 type NADPH oxidase in angiogenic responses in human microvascular endothelial cells in vitro. Arterioscler Thromb Vasc Biol. 2007;27:2319-2324. doi: 10.1161/ATVBAHA.107.149450.
52. Grgic I, Eichler I, Heinau P, Si H, Brakemeier S, Hoyer J, Köhler R. Selective blockade of the intermediate-conductance Ca2+-activated K+ channel suppresses proliferation of microvascular and macrovascular endothelial cells and angiogenesis in vivo. Arterioscler Thromb Vasc Biol. 2005;25:704-709. doi: 10.1161/01.ATV.0000156399.12787.5c.
53. Durand MJ, Phillips SA, Widlansky ME, Otterson MF, Gutterman DD. The vascular renin-angiotensin system contributes to blunted vasodilation induced by transient high pressure in human adipose microvessels. Am J Physiol Heart Circ Physiol. 2014;307:H25-H32. doi: 10.1152/ajpheart.00055.2014.
54. Paraskevaidis IA, Iliodromitis EK, Ikonomidis I, Rallidis L, Hamodraka E, Parissis J, Andoniadis A, Tzortzis S, Anastasiou-Nana M. The effect of acute administration of statins on coronary microcirculation during the pre-revascularization period in patients with myocardial infraction. Atherosclerosis. 2012;223:184-189. doi: 10.1016/j. atherosclerosis.2012.04.002.
55. Larsen BT, Miura H, Hatoum OA, Campbell WB, Hammock BD, Zeldin DC, Falck JR, Gutterman DD. Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BK(Ca) channels: implications for soluble epoxide hydrolase inhibition. Am J Physiol Heart Circ Physiol. 2006;290:H491-H499. doi: 10.1152/ajpheart.00927.2005.
56. Dhanasekaran A, Al-Saghir R, Lopez B, Zhu D, Gutterman DD, Jacobs ER, Medhora M. Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature. Am J Physiol Heart Circ Physiol. 2006;291:H517-H531. doi: 10.1152/ajpheart.00953.2005.
57. Tacconelli S, Patrignani P. Inside epoxyeicosatrienoic acids and cardiovascular disease. Front Pharmacol. 2014;5:239. doi: 10.3389/fphar.2014.00239.
58. Yoshino S, Cilluffo R, Best PJ, Atkinson EJ, Aoki T, Cunningham JM, de Andrade M, Choi BJ, Lerman LO, Lerman A. Single nucleotide polymorphisms associated with abnormal coronary microvascular function. Coron Artery Dis. 2014;25:281-289. doi: 10.1097/MCA.0000000000000104.
59. Fedele F, Mancone M, Chilian WM, Severino P, Canali E, Logan S, De Marchis ML, Volterrani M, Palmirotta R, Guadagni F. Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease. Basic Res Cardiol. 2013;108:387. doi: 10.1007/s00395-013-0387-4.
60. Mashiba J, Koike G, Kamiunten H, Ikeda M, Sunagawa K. Vasospastic angina and microvascular angina are differentially influenced by PON1 A632G polymorphism in the Japanese. Circ J. 2005;69:1466-1471.
61. Ekmekci A, Güngör B, Özcan KS, Abaci N, Ilhan E, Ekmekci SS, Kemalolu T, Osmonov D, Ustek D, Eren M. Evaluation of coronary microvascular function and nitric oxide synthase intron 4a/b polymorphism in patients with coronary slow flow. Coron Artery Dis. 2013;24:461-467. doi: 10.1097/MCA.0b013e328363258c.
62. Katoh A, Ikeda H, Takajo Y, Haramaki N, Murohara T, Shintani S, Kanaya S, Yokoyama S, Ueno T, Honma T, Imaizumi T. Coexistence of impairment of endothelium-derived nitric oxide and platelet-derived nitric oxide in patients with coronary risk factors. Circ J. 2002;66:837-840.
63. Al-Fiadh AH, Farouque O, Kawasaki R, Nguyen TT, Uddin N, Freeman M, Patel SK, Burrell LM, Wong TY. Retinal microvascular structure and function in patients with risk factors of atherosclerosis and coronary artery disease. Atherosclerosis. 2014;233:478-484. doi: 10.1016/j. atherosclerosis.2013.12.044.
64. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, deLaGrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC, Selwyn AP. Close relation of endothelial function in the human coronary and peripheral circulations. JAmCollCardiol. 1995;26:1235-1241.
65. Kunadian V, Harrigan C, Zorkun C, Palmer AM, Ogando KJ, Biller LH, Lord EE, Williams SP, Lew ME, Ciaglo LN, Buros JL, Marble SJ, Gibson WJ, Gibson CM. Use of the TIMI frame count in the assessment of coronary artery blood flow and microvascular function over the past 15 years. J Thromb Thrombolysis. 2009;27:316-328. doi: 10.1007/s11239-008-0220-3.
66. Hamada S, Nishiue T, Nakamura S, Sugiura T, Kamihata H, Miyoshi H, Imuro Y, Iwasaka T. TIMI frame count immediately after primary coronary angioplasty as a predictor of functional recovery in patients with TIMI 3 reperfused acute myocardial infarction. J Am Coll Cardiol. 2001;38:666-671.
67. Gibson CM, Murphy SA, Rizzo MJ, Ryan KA, Marble SJ, McCabe CH, Cannon CP, Van de Werf F, Braunwald E. Relationship between TIMI frame count and clinical outcomes after thrombolytic administration. Thrombolysis In Myocardial Infarction (TIMI) Study Group. Circulation. 1999;99:1945-1950.
68. Strain WD, Adingupu DD, Shore AC. Microcirculation on a large scale: techniques, tactics and relevance of studying the microcirculation in larger population samples. Microcirculation. 2012;19:37-46. doi: 10.1111/j.1549-8719.2011.00140.x.
69. Wei K, Lindner J. Contrast ultrasound in the assessment of patients presenting with suspected cardiac ischemia. Crit Care Med. 2007;35:S280-S289. doi: 10.1097/01.CCM.0000260678.03628.4C.
70. Miller FJ Jr, Dellsperger KC, Gutterman DD. Myogenic constriction of human coronary arterioles. Am J Physiol. 1997;273:H257-H264.
71. Cohen MV, Kirk ES. Differential response of large and small coronary arteries to nitroglycerin and angiotensin. CircRes. 1973;18:445-453.
72. Penny WF, Rockman H, Long J, Bhargava V, Carrigan K, Ibriham A, Shabetai R, Ross J Jr, Peterson KL. Heterogeneity of vasomotor response to acetylcholine along the human coronary artery. J Am Coll Cardiol. 1995;25:1046-1055.
73. Kuo L, Davis MJ, Chilian WM. Endothelium-dependent, flowinduced dilation of isolated coronary arterioles. Am J Physiol. 1990;259:H1063-H1070.
74. Koller A, Kaley G. Prostaglandins mediate arteriolar dilation to increased blood flow velocity in skeletal muscle microcirculation. Circ Res. 1990;67:529-534.
75. Huang A, Sun D, Carroll MA, Jiang H, Smith CJ, Connetta JA, Falck JR, Shesely EG, Koller A, Kaley G. EDHF mediates flow-induced dilation in skeletal muscle arterioles of female eNOS-KO mice. Am J Physiol Heart Circ Physiol. 2001;280:H2462-H2469.
76. Myers PR, Banitt PF, Guerra R Jr, Harrison DG. Role of the endothelium in modulation of the acetylcholine vasoconstrictor response in porcine coronary microvessels. Cardiovasc Res. 1991;25:129-137.
77. Brunori M, Giuffrè A, Sarti P, Stubauer G, Wilson MT. Nitric oxide and cellular respiration. Cell Mol Life Sci. 1999;56:549-557.
78. Brookes PS, Kraus DW, Shiva S, Doeller JE, Barone MC, Patel RP, Lancaster JR Jr, Darley-Usmar V. Control of mitochondrial respiration by NO, effects of low oxygen and respiratory state. J Biol Chem. 2003;278:31603-31609. doi: 10.1074/jbc.M211784200.
79. Yao SK, Ober JC, Krishnaswami A, Ferguson JJ, Anderson HV, Golino P, Buja LM, Willerson JT. Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endotheliuminjured arteries. Circulation. 1992;86:1302-1309.
80. Broeders MA, Tangelder GJ, Slaaf DW, Reneman RS, oude Egbrink MG. Endogenous nitric oxide protects against thromboembolism in venules but not in arterioles. Arterioscler Thromb Vasc Biol. 1998;18:139-45.
81. Noireaud J, Andriantsitohaina R. Recent insights in the paracrine modulation of cardiomyocyte contractility by cardiac endothelial cells. Biomed Res Int. 2014;2014:923805. doi: 10.1155/2014/923805.
82. Namekata I, Fujiki S, Kawakami Y, Moriwaki R, Takeda K, Kawanishi T, Takahara A, Shigenobu K, Tanaka H. Intracellular mechanisms and receptor types for endothelin-1-induced positive and negative inotropy in mouse ventricular myocardium. Naunyn Schmiedebergs Arch Pharmacol. 2008;376:385-395. doi: 10.1007/s00210-007-0228-9.
83. Harder DR, Campbell WB and Roman RJ. Role of cytochrome P-450 enzymes and metabolites of arachidonic acid in the control of vascular tone. J Vasc Res. 1995;32:79-92.
84. Larsen BT, Bubolz AH, Mendoza SA, Pritchard KA Jr, Gutterman DD. Bradykinin-induced dilation of human coronary arterioles requires NADPH oxidase-derived reactive oxygen species. Arterioscler Thromb Vasc Biol. 2009;29:739-745. doi: 10.1161/ATVBAHA.108.169367.
85. Miura H, Wachtel RE, Liu Y, Loberiza FR Jr, Saito T, Miura M, Gutterman DD. Flow-induced dilation of human coronary arterioles: important role of Ca(2+)-activated K(+) channels. Circulation. 2001;103:1992-1998.
86. Ungvari Z, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith K, Csiszar A. Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am J Physiol Heart Circ Physiol. 2007;293:H37-H47. doi: 10.1152/ajpheart.01346.2006.
87. Bychkov R, Pieper K, Ried C, Milosheva M, Bychkov E, Luft FC, Haller H. Hydrogen peroxide, potassium currents, and membrane potential in human endothelial cells. Circulation. 1999;99:1719-1725.
88. Ody C, Junod AF. Effect of variable glutathione peroxidase activity on H2O2-related cytotoxicity in cultured aortic endothelial cells. Proc Soc Exp Biol Med. 1985;180:103-111.
89. Witting PK, Rayner BS, Wu BJ, Ellis NA, Stocker R. Hydrogen peroxide promotes endothelial dysfunction by stimulating multiple sources of superoxide anion radical production and decreasing nitric oxide bioavailability. Cell Physiol Biochem. 2007;20:255-268. doi: 10.1159/000107512.
90. Talukdar S, Oh da Y, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J, Lin M, Brenner MB, Olefsky JM. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012;18:1407-1412. doi: 10.1038/nm.2885.
91. Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, Wang ZV, Landskroner-Eiger S, Dineen S, Magalang UJ, Brekken RA, Scherer PE. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009;29:4467-4483. doi: 10.1128/MCB.00192-09.
92. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, von Schlippenbach J, Skurk C, Steendijk P, Riad A, Poller W, Schultheiss HP, Tschöpe C. Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail. 2011;4:44-52. doi: 10.1161/CIRCHEARTFAILURE.109.931451.
93. Tschöpe C, Bock CT, Kasner M, Noutsias M, Westermann D, Schwimmbeck PL, Pauschinger M, Poller WC, Kühl U, Kandolf R, Schultheiss HP. High prevalence of cardiac parvovirus B19 infection in patients with isolated left ventricular diastolic dysfunction. Circulation. 2005;111:879-886. doi: 10.1161/01.CIR.0000155615.68924.B3.
94. Hugel B, Martínez MC, Kunzelmann C, Freyssinet JM. Membrane microparticles: two sides of the coin. Physiology (Bethesda). 2005;20:22-27. doi: 10.1152/physiol.00029.2004.
95. Dignat-George F, Boulanger CM. The many faces of endothelial microparticles. Arterioscler Thromb Vasc Biol. 2011;31:27-33. doi: 10.1161/ATVBAHA.110.218123.
96. Boulanger CM, Scoazec A, Ebrahimian T, Henry P, Mathieu E, Tedgui A, Mallat Z. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation. 2001;104:2649-2652.
97. Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, Hristov M, Köppel T, Jahantigh MN, Lutgens E, Wang S, Olson EN, Schober A, Weber C. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal. 2009;2:81. doi: 10.1126/scisignal.2000610.
98. Seddon MD, Chowienczyk PJ, Brett SE, Casadei B, Shah AM. Neuronal nitric oxide synthase regulates basal microvascular tone in humans in vivo. Circulation. 2008;117:1991-1996. doi: 10.1161/CIRCULATIONAHA.107.744540.
99. Melikian N, Seddon MD, Casadei B, Chowienczyk PJ, Shah AM. Neuronal nitric oxide synthase and human vascular regulation. Trends Cardiovasc Med. 2009;19:256-262. doi: 10.1016/j.tcm.2010.02.007.
100. Seddon M, Melikian N, Dworakowski R, Shabeeh H, Jiang B, Byrne J, Casadei B, Chowienczyk P, Shah AM. Effects of neuronal nitric oxide synthase on human coronary artery diameter and blood flow in vivo. Circulation. 2009;119:2656-2662. doi: 10.1161/CIRCULATIONAHA.108.822205.
101. Lamping KG, Nuno DW, Faraci FM. Role of nNOS in dilation to acetylcholine in coronary arteries from eNOS-deficient mice. Faseb J. 1999:A1085.
102. Huang A, Sun D, Shesely EG, Levee EM, Koller A, Kaley G. Neuronal NOS-dependent dilation to flow in coronary arteries of male eNOS-KO mice. Am J Physiol Heart Circ Physiol. 2002;282:H429-H436. doi: 10.1152/ajpheart.00501.2001.
103. Fischer D, Landmesser U, Spiekermann S, Hilfiker-Kleiner D, Hospely M, Müller M, Busse R, Fleming I, Drexler H. Cytochrome P450 2C9 is involved in flow-dependent vasodilation of peripheral conduit arteries in healthy subjects and in patients with chronic heart failure. Eur J Heart Fail. 2007;9:770-775. doi: 10.1016/j.ejheart.2007.05.005.
104. Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol. 2003;41:1769-1775.
105. Patti G, Pasceri V, Melfi R, Goffredo C, Chello M, D'Ambrosio A, Montesanti R, Di Sciascio G. Impaired flow-mediated dilation and risk of restenosis in patients undergoing coronary stent implantation. Circulation. 2005;111:70-75. doi: 10.1161/01.CIR.0000151308.06673.D2.
106. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Münzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001;104:2673-2678.
107. Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101:1899-1906.
108. Jurva JW, Phillips SA, Syed AQ, Syed AY, Pitt S, Weaver A, Gutterman DD. The effect of exertional hypertension evoked by weight lifting on vascular endothelial function. J Am Coll Cardiol. 2006;48:588-589. doi: 10.1016/j.jacc.2006.05.004.
109. Title LM, Cummings PM, Giddens K, Nassar BA. Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E. J Am Coll Cardiol. 2000;36:2185-2191.
110. Dharmashankar K, Welsh A, Wang J, Kizhakekuttu TJ, Ying R, Gutterman DD, Widlansky ME. Nitric oxide synthase-dependent vasodilation of human subcutaneous arterioles correlates with noninvasive measurements of endothelial function. Am J Hypertens. 2012;25:528-534. doi: 10.1038/ajh.2012.8.
111. Cooper A, Heagerty AM. Endothelial dysfunction in human intramyocardial small arteries in atherosclerosis and hypercholesterolemia. Am J Physiol. 1998;275:H1482-H1488.
112. Miura H, Liu Y, Gutterman DD. Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization. Circulation. 1999;99:3132-3138.
113. Kichuk MR, Zhang X, Oz M, Michler R, Kaley G, Nasjletti A, Hintze TH. Angiotensin-converting enzyme inhibitors promote nitric oxide production in coronary microvessels from failing explanted human hearts. Am J Cardiol. 1997;80:137A-142A.
114. Tiefenbacher CP, Friedrich S, Bleeke T, Vahl C, Chen X, Niroomand F. ACE inhibitors and statins acutely improve endothelial dysfunction of human coronary arterioles. Am J Physiol Heart Circ Physiol. 2004;286:H1425-H1432. doi: 10.1152/ajpheart.00783.2003.
115. Tiefenbacher CP, Bleeke T, Vahl C, Amann K, Vogt A, Kubler W. Endothelial dysfunction of coronary resistance arteries is improved by tetrahydrobiopterin in atherosclerosis. Circulation. 2000;102:2172-2179.
116. Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, Kanaide H, Takeshita A. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest. 2000;106:1521-1530. doi: 10.1172/JCI10506.
117. Zinkevich NS, Wittenburg AL, Gutterman DD. Role of cyclooxygenase in flow-induced dilation of human coronary arterioles depends upone age. Circulation. 2010;122.
118. Miura H, Qiang C, Liu Y, Saito T, Miura M, Gutterman DD. Flowmediated dilation of human coronary arterioles involves production of hydrogen peroxide. Circulation. 2001;104:II-285-II-286.
119. Liu Y, Zhao H, Li H, Kalyanaraman B, Nicolosi AC, Gutterman DD. Mitochondrial sources of H2O2 generation play a key role in flowmediated dilation in human coronary resistance arteries. Circ Res. 2003;93:573-580. doi: 10.1161/01.RES.0000091261.19387.AE.
120. Burgoyne JR, Oka S, Ale-Agha N, Eaton P. Hydrogen peroxide sensing and signaling by protein kinases in the cardiovascular system. Antioxid Redox Signal. 2013;18:1042-1052. doi: 10.1089/ars.2012.4817.
121. Bubolz AH, Mendoza SA, Zheng X, Zinkevich NS, Li R, Gutterman DD, Zhang DX. Activation of endothelial TRPV4 channels mediates flow-induced dilation in human coronary arterioles: role of Ca2+ entry and mitochondrial ROS signaling. Am J Physiol Heart Circ Physiol. 2012;302:H634-H642. doi: 10.1152/ajpheart.00717.2011.
122. Liu Y, Li H, Bubolz AH, Zhang DX, Gutterman DD. Endothelial cytoskeletal elements are critical for flow-mediated dilation in human coronary arterioles. Med Biol Eng Comput. 2008;46:469-478. doi: 10.1007/s11517-008-0331-1.
123. Kurek K, Piotrowska DM, Wiesiolek-Kurek P, Chabowska A, Lukaszuk B, Zendzian-Piotrowska M. The role of sphingolipids in selected cardiovascular diseases. Postepy Hig Med Dosw (Online). 2013;67:1018-26.
124. Li X, Becker KA, Zhang Y. Ceramide in redox signaling and cardiovascular diseases. Cell Physiol Biochem. 2010;26:41-48. doi: 10.1159/000315104.
125. Bismuth J, Lin P, Yao Q, Chen C. Ceramide: a common pathway for atherosclerosis Atherosclerosis. 2008;196:497-504. doi: 10.1016/j. atherosclerosis.2007.09.018.
126. Deshpande SS, Qi B, Park YC, Irani K. Constitutive activation of rac1 results in mitochondrial oxidative stress and induces premature endothelial cell senescence. Arterioscler Thromb Vasc Biol. 2003;23:e1-e6.
127. Corda S, Laplace C, Vicaut E, Duranteau J. Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-alpha is mediated by ceramide. Am J Respir Cell Mol Biol. 2001;24:762-768. doi: 10.1165/ajrcmb.24.6.4228.
128. Czarny M, Liu J, Oh P, Schnitzer JE. Transient mechanoactivation of neutral sphingomyelinase in caveolae to generate ceramide. J Biol Chem. 2003;278:4424-4430. doi: 10.1074/jbc.M210375200.
129. Freed JK, Beyer AM, LoGiudice JA, Hockenberry JC, Gutterman DD. Ceramide changes the mediator of flow-induced vasodilation from nitric oxide to hydrogen peroxide in the human microcirculation. Circ Res. 2014;115:525-532. doi: 10.1161/CIRCRESAHA.115.303881.
130. Wooten-Blanks LG, Song P, Senkal CE, Ogretmen B. Mechanisms of ceramide-mediated repression of the human telomerase reverse transcriptase promoter via deacetylation of Sp3 by histone deacetylase 1. FASEB J. 2007;21:3386-3397. doi: 10.1096/fj.07-8621com.
131. Santos JH, Meyer JN, Van Houten B. Mitochondrial localization of telomerase as a determinant for hydrogen peroxide-induced mitochondrial DNA damage and apoptosis. Hum Mol Genet. 2006;15:1757-1768. doi: 10.1093/hmg/ddl098.
132. Haendeler J, Dröse S, Büchner N, Jakob S, Altschmied J, Goy C, Spyridopoulos I, Zeiher AM, Brandt U, Dimmeler S. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol. 2009;29:929-935. doi: 10.1161/ATVBAHA.109.185546.
133. Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, Tsao PS. eNOS activity is reduced in senescent human endothelial cells: Preservation by hTERT immortalization. Circ Res. 2001;89:793-798.
134. Sahin E, Depinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature. 2010;464:520-528. doi: 10.1038/nature08982.
135. Sahin E, Colla S, Liesa M, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011;470:359-365. doi: 10.1038/nature09787.
136. Santos J, Gutterman DD, Beyer AM. Mitochondrial telomerase regulates flow mediated dilation by suppressing mitochondrial derived free radical production. FASEB J. 2014;28:664.1.
137. Eitan E, Tichon A, Gazit A, Gitler D, Slavin S, Priel E. Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis. EMBO Mol Med. 2012;4:313-329. doi: 10.1002/emmm.201200212.
138. Beyer AM, Gutterman DD. Activation of PPAR {gamma} converts the mechanism of flow-mediated dilation in human microvessels from H2O2 to NO by a telomerase dependent mechanism. Circulation. 2012;126:A9240.
139. Myers PR, Banitt PF, Guerra R Jr, Harrison DG. Characteristics of canine coronary resistance arteries: importance of endothelium. Am J Physiol. 1989;257:H603-H610.
140. Broten TP, Miyashiro JK, Moncada S, Feigl EO. Role of endotheliumderived relaxing factor in parasympathetic coronary vasodilation. Am J Physiol. 1992;262:H1579-H1584.
141. Miller FJ Jr, Dellsperger KC, Gutterman DD. Pharmacologic activation of the human coronary microcirculation in vitro: endothelium-dependent dilation and differential responses to acetylcholine. Cardiovasc Res. 1998;38:744-750.
142. Angus JA, Cocks TM, McPherson GA, Broughton A. The acetylcholine paradox: a constrictor of human small coronary arteries even in the presence of endothelium. Clin Exp Pharmacol Physiol. 1991;18:33-36.
143. Terata K, Miura H, Liu Y, Loberiza F, Gutterman DD. Human coronary arteriolar dilation to adrenomedullin: role of nitric oxide and K(+) channels. Am J Physiol Heart Circ Physiol. 2000;279:H2620-H2626.
144. Sueda S, Fukuda H, Watanabe K, Ochi N, Kawada H, Hayashi Y, Uraoka T. Clinical characteristics and possible mechanism of paroxysmal atrial fibrillation induced by intracoronary injection of acetylcholine. Am J Cardiol. 2001;88:570-573.
145. Sato A, Miura H, Liu Y, Somberg LB, Otterson MF, Demeure MJ, Schulte WJ, Eberhardt LM, Loberiza FR, Sakuma I, Gutterman DD. Effect of gender on endothelium-dependent dilation to bradykinin in human adipose microvessels. Am J Physiol Heart Circ Physiol. 2002;283:H845-H852. doi: 10.1152/ajpheart.00160.2002.
146. Miura H, Liu Y, Gutterman DD. Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization. Contribution of nitric oxide and calcium-activated K+ channels. Circulation. 1999;99: 3132-3138.
147. Larsen BT, Gutterman DD, Sato A, Toyama K, Campbell WB, Zeldin DC, Manthati VL, Falck JR, Miura H. Hydrogen peroxide inhibits cytochrome p450 epoxygenases: interaction between two endothelium-derived hyperpolarizing factors. Circ Res. 2008;102:59-67. doi: 10.1161/CIRCRESAHA.107.159129.
148. Ding Z, Gödecke A, Schrader J. Contribution of cytochrome P450 metabolites to bradykinin-induced vasodilation in endothelial NO synthase deficient mouse hearts. Br J Pharmacol. 2002;135:631-638. doi: 10.1038/sj.bjp.0704472.
149. Quayle JM, Nelson MT, Standen NB. ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev. 1997;77:1165-1232.
150. Lynch FM, Austin C, Heagerty AM, Izzard AS. Adenosine-and hypoxiainduced dilation of human coronary resistance arteries: evidence against the involvement of K(ATP) channels. Br J Pharmacol. 2006;147:455-458. doi: 10.1038/sj.bjp.0706622.
151. Kemp BK, Cocks TM. Adenosine mediates relaxation of human small resistance-like coronary arteries via A2B receptors. Br J Pharmacol. 1999;126:1796-1800. doi: 10.1038/sj.bjp.0702462.
152. Sato A, Terata K, Miura H, Toyama K, Loberiza FR Jr, Hatoum OA, Saito T, Sakuma I, Gutterman DD. Mechanism of vasodilation to adenosine in coronary arterioles from patients with heart disease. Am J Physiol Heart Circ Physiol. 2005;288:H1633-H1640. doi: 10.1152/ajpheart.00575.2004.
153. Miura H, Wachtel RE, Loberiza FR Jr, Saito T, Miura M, Nicolosi AC, Gutterman DD. Diabetes mellitus impairs vasodilation to hypoxia in human coronary arterioles: reduced activity of ATP-sensitive potassium channels. Circ Res. 2003;92:151-158.
154. Beyer AM, Durand MJ, Hockenberry J, Gamblin TC, Phillips SA, Gutterman DD. An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles. Am J Physiol Heart Circ Physiol. 2014;307:H1587-H1593. doi: 10.1152/ajpheart.00557.2014.
155. Matoba T, Shimokawa H, Kubota H, Morikawa K, Fujiki T, Kunihiro I, Mukai Y, Hirakawa Y, Takeshita A. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries. Biochem Biophys Res Commun. 2002;290:909-913. doi: 10.1006/bbrc.2001.6278.
156. Morikawa K, Shimokawa H, Matoba T, Kubota H, Akaike T, Talukder MA, Hatanaka M, Fujiki T, Maeda H, Takahashi S, Takeshita A. Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization. J Clin Invest. 2003;112:1871-1879. doi: 10.1172/JCI19351.
157. Hatoum OA, Binion DG, Otterson MF, Gutterman DD. Acquired microvascular dysfunction in inflammatory bowel disease: loss of nitric oxidemediated vasodilation. Gastroenterology. 2003;125:58-69.
158. Singh A, Donnino R, Weintraub H, Schwartzbard A. Effect of strict glycemic control in patients with diabetes mellitus on frequency of macrovascular events. Am J Cardiol. 2013;112:1033-1038. doi: 10.1016/j. amjcard.2013.05.044.
159. Feng J, Liu Y, Chu LM, Singh AK, Dobrilovic N, Fingleton JG, Clements RT, Bianchi C, Sellke FW. Changes in microvascular reactivity after cardiopulmonary bypass in patients with poorly controlled versus controlled diabetes. Circulation. 2012;126:S73-S80. doi: 10.1161/CIRCULATIONAHA.111.084590.
160. Shida T, Nozawa T, Sobajima M, Ihori H, Matsuki A, Inoue H. Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature. Heart Vessels. 2014;29:532-541. doi: 10.1007/s00380-013-0402-6.
161. Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A, Gross RW, Kelly DP. A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci USA. 2003;100:1226-1231. doi: 10.1073/pnas.0336724100.
162. Dessy C, Moniotte S, Ghisdal P, Havaux X, Noirhomme P, Balligand JL. Endothelial beta3-adrenoceptors mediate vasorelaxation of human coronary microarteries through nitric oxide and endothelium-dependent hyperpolarization. Circulation. 2004;110:948-954. doi: 10.1161/01. CIR.0000139331.85766.AF.
163. Zinkevich NS, Wittenburg AL, Gutterman DD. Role of cyclooxygenase in flow-induced dilation of human coronary arterioles depends upon age. Circulation. 2010;122:A15764. Abstract. http://circ.ahajournals. org/cgi/content/meeting-abstract/122/21-MeetingAbstracts/A15764.
164. Kichuk MR, Seyedi N, Zhang X, Marboe CC, Michler RE, Addonizio LJ, Kaley G, Nasjletti A, Hintze TH. Regulation of nitric oxide production in human coronary microvessels and the contribution of local kinin formation. Circulation. 1996;94:44-51.
165. Rubin MA, Putzi M, Mucci N, Smith DC, Wojno K, Korenchuk S, Pienta KJ. Rapid ("warm") autopsy study for procurement of metastatic prostate cancer. Clin Cancer Res. 2000;6:1038-1045.
166. Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol. 1995;268:C799-C822.
167. Ko EA, Han J, Jung ID, Park WS. Physiological roles of K+ channels in vascular smooth muscle cells. J Smooth Muscle Res. 2008;44:65-81.
168. Wilde DW, Lee KS. Outward potassium currents in freshly isolated smooth muscle cell of dog coronary arteries. Circ Res. 1989;65: 1718-1734.
169. Aiello EA, Clement-Chomienne O, Sontag DP, Walsh MP, Cole WC. Protein kinase C inhibits delayed rectifier K+ current in rabbit vascular smooth muscle cells. Am J Physiol. 1996;271:H109-H119.
170. Rogers PA, Dick GM, Knudson JD, Focardi M, Bratz IN, Swafford AN Jr, Saitoh S, Tune JD, Chilian WM. H2O2-induced redox-sensitive coronary vasodilation is mediated by 4-aminopyridine-sensitive K+ channels. Am J Physiol Heart Circ Physiol. 2006;291:H2473-H2482. doi: 10.1152/ajpheart.00172.2006.
171. Brayden JE, Nelson MT. Regulation of arterial tone by activation of calcium-dependent potassium channels. Science. 1992;256:532-535.
172. Archer SL, Gragasin FS, Wu X, Wang S, McMurtry S, Kim DH, Platonov M, Koshal A, Hashimoto K, Campbell WB, Falck JR, Michelakis ED. Endothelium-derived hyperpolarizing factor in human internal mammary artery is 11,12-epoxyeicosatrienoic acid and causes relaxation by activating smooth muscle BK(Ca) channels. Circulation. 2003;107:769-776.
173. Fürstenau M, Löhn M, Ried C, Luft FC, Haller H, Gollasch M. Calcium sparks in human coronary artery smooth muscle cells resolved by confocal imaging. J Hypertens. 2000;18:1215-1222.
174. Li Z, Lu N, Shi L. Exercise training reverses alterations in Kv and BKCa channel molecular expression in thoracic aorta smooth muscle cells from spontaneously hypertensive rats. J Vasc Res. 2014;51:447-457. doi: 10.1159/000369928.
175. Jackson WF. Potassium channels in the peripheral microcirculation. Microcirculation. 2005;12:113-127. doi: 10.1080/10739680590896072.
176. Stephens GJ, Owen DG, Robertson B. Cysteine-modifying reagents alter the gating of the rat cloned potassium channel Kv1.4. Pflugers Arch. 1996;431:435-442.
177. Duprat F, Guillemare E, Romey G, Fink M, Lesage F, Lazdunski M, Honore E. Susceptibility of cloned K+ channels to reactive oxygen species. Proc Natl Acad Sci USA. 1995;92:11796-11800.
178. Li X, Tang K, Xie B, Li S, Rozanski GJ. Regulation of Kv4 channel expression in failing rat heart by the thioredoxin system. Am J Physiol Heart Circ Physiol. 2008;295:H416-H424. doi: 10.1152/ajpheart.91446.2007.
179. Mittal M, Gu XQ, Pak O, Pamenter ME, Haag D, Fuchs DB, Schermuly RT, Ghofrani HA, Brandes RP, Seeger W, Grimminger F, Haddad GG, Weissmann N. Hypoxia induces Kv channel current inhibition by increased NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med. 2012;52:1033-1042. doi: 10.1016/j. freeradbiomed.2011.12.004.
180. Jerng HH, Pfaffinger PJ. S-glutathionylation of an auxiliary subunit confers redox sensitivity to Kv4 channel inactivation. PLoS One. 2014;9:e93315. doi: 10.1371/journal.pone.0093315.
181. Li H, Chai Q, Gutterman DD, Liu Y. Elevated glucose impairs cAMPmediated dilation by reducing Kv channel activity in rat small coronary smooth muscle cells. Am J Physiol Heart Circ Physiol. 2003;285:H1213-H1219. doi: 10.1152/ajpheart.00226.2003.
182. Liu Y, Gutterman DD. The coronary circulation in diabetes: influence of reactive oxygen species on K+ channel-mediated vasodilation. Vascul Pharmacol. 2002;38:43-49.
183. Liu Y, Terata K, Rusch NJ, Gutterman DD. High glucose impairs voltage-gated K(+) channel current in rat small coronary arteries. Circ Res. 2001;89:146-152.
184. Li H, Gutterman DD, Rusch NJ, Bubolz A, Liu Y. Nitration and functional loss of voltage-gated K+ channels in rat coronary microvessels exposed to high glucose. Diabetes. 2004;53:2436-2442.
185. Heaps CL, Tharp DL, Bowles DK. Hypercholesterolemia abolishes voltage-dependent K+ channel contribution to adenosine-mediated relaxation in porcine coronary arterioles. Am J Physiol Heart Circ Physiol. 2005;288:H568-H576. doi: 10.1152/ajpheart.00157.2004.
186. Heaps CL, Jeffery EC, Laine GA, Price EM, Bowles DK. Effects of exercise training and hypercholesterolemia on adenosine activation of voltage-dependent K+ channels in coronary arterioles. J Appl Physiol (1985). 2008;105:1761-1771. doi: 10.1152/japplphysiol.90958.2008.
187. Caouette D, Dongmo C, Bérubé J, Fournier D, Daleau P. Hydrogen peroxide modulates the Kv1.5 channel expressed in a mammalian cell line. Naunyn Schmiedebergs Arch Pharmacol. 2003;368:479-486. doi: 10.1007/s00210-003-0834-0.
188. Platoshyn O, Yu Y, Golovina VA, McDaniel SS, Krick S, Li L, Wang JY, Rubin LJ, Yuan JX. Chronic hypoxia decreases K(V) channel expression and function in pulmonary artery myocytes. Am J Physiol Lung Cell Mol Physiol. 2001;280:L801-L812.
189. Wang J, Weigand L, Wang W, Sylvester JT, Shimoda LA. Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery. Am J Physiol Lung Cell Mol Physiol. 2005;288:L1049-L1058. doi: 10.1152/ajplung.00379.2004.
190. Fountain SJ, Cheong A, Li J, Dondas NY, Zeng F, Wood IC, Beech DJ. K(v)1.5 potassium channel gene regulation by Sp1 transcription factor and oxidative stress. Am J Physiol Heart Circ Physiol. 2007;293:H2719-H2725. doi: 10.1152/ajpheart.00637.2007.
191. Park SW, Noh HJ, Sung DJ, Kim JG, Kim JM, Ryu SY, Kang K, Kim B, Bae YM, Cho H. Hydrogen peroxide induces vasorelaxation by enhancing 4-aminopyridine-sensitive Kv currents through S-glutathionylation. Pflugers Arch. 2014;467:285-297. doi: 10.1007/s00424-014-1513-3.
192. Cogolludo A, Frazziano G, Cobenõ L, Moreno L, Lodi F, Villamor E, Tamargo J, Perez-Vizcaino F. Role of reactive oxygen species in Kv channel inhibition and vasoconstriction induced by TP receptor activation in rat pulmonary arteries. Ann N Y Acad Sci. 2006;1091:41-51. doi: 10.1196/annals.1378.053.
193. Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK. Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol. 2008;294:H570-H578. doi: 10.1152/ajpheart.01324.2007.
194. Svoboda LK, Reddie KG, Zhang L, Vesely ED, Williams ES, Schumacher SM, O'Connell RP, Shaw R, Day SM, Anumonwo JM, Carroll KS, Martens JR. Redox-sensitive sulfenic acid modification regulates surface expression of the cardiovascular voltage-gated potassium channel Kv1.5. Circ Res. 2012;111:842-853. doi: 10.1161/CIRCRESAHA.111.263525.
195. Adda S, Fleischmann BK, Freedman BD, Yu M, Hay DW, Kotlikoff MI. Expression and function of voltage-dependent potassium channel genes in human airway smooth muscle. J Biol Chem. 1996;271:13239-13243.
196. Brundel BJ, Van Gelder IC, Henning RH, Tieleman RG, Tuinenburg AE, Wietses M, Grandjean JG, Van Gilst WH, Crijns HJ. Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation. 2001;103:684-690.
197. Van Wagoner DR, Pond AL, McCarthy PM, Trimmer JS, Nerbonne JM. Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. Circ Res. 1997;80:772-781.
198. Ohanyan V, Yin L, Bardakjian R, et al. Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation. Circ Res. 2015;117:612-621. doi: 10.1161/CIRCRESAHA.115.306642.
199. Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol. 1995;268:C799-C822.
200. Carl A, Lee HK, Sanders KM. Regulation of ion channels in smooth muscles by calcium. Am J Physiol. 1996;271:C9-34.
201. Jackson WF, Huebner JM, Rusch NJ. Enzymatic isolation and characterization of single vascular smooth muscle cells from cremasteric arterioles. Microcirculation. 1997;4:35-50.
202. Jackson WF, Blair KL. Characterization and function of Ca(2+)-activated K+ channels in arteriolar muscle cells. Am J Physiol. 1998;274:H27-H34.
203. Li PL, Jin MW, Campbell WB. Effect of selective inhibition of soluble guanylyl cyclase on the K(Ca) channel activity in coronary artery smooth muscle. Hypertension. 1998;31:303-308.
204. Zhu S, Han G, White RE. PGE2 action in human coronary artery smooth muscle: role of potassium channels and signaling cross-talk. J Vasc Res. 2002;39:477-488.
205. White RE, Kryman JP, El-Mowafy AM, Han G, Carrier GO. cAMP-dependent vasodilators cross-activate the cGMP-dependent protein kinase to stimulate BK(Ca) channel activity in coronary artery smooth muscle cells. Circ Res. 2000;86:897-905.
206. Campbell WB, Gebremedhin D, Pratt PF, Harder DR. Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res. 1996;78:415-423.
207. Xi Q, Cheranov SY, Jaggar JH. Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca2+ sparks. Circ Res. 2005;97:354-362. doi: 10.1161/01.RES.0000177669.29525.78.
208. Asano M, Matsuda T, Hayakawa M, Ito KM, Ito K. Increased resting Ca2+ maintains the myogenic tone and activates K+ channels in arteries from young spontaneously hypertensive rats. Eur J Pharmacol. 1993;247:295-304.
209. Liu Y, Pleyte K, Knaus HG, Rusch NJ. Increased expression of Ca2+-sensitive K+ channels in aorta of hypertensive rats. Hypertension. 1997;30:1403-1409.
210. Liu Y, Hudetz AG, Knaus HG, Rusch NJ. Increased expression of Ca2+-sensitive K+ channels in the cerebral microcirculation of genetically hypertensive rats: evidence for their protection against cerebral vasospasm. CircRes. 1998;82:729-737.
211. Wiecha J, Schläger B, Voisard R, Hannekum A, Mattfeldt T, Hombach V. Ca(2+)-activated K+ channels in human smooth muscle cells of coronary atherosclerotic plaques and coronary media segments. Basic Res Cardiol. 1997;92:233-239.
212. Lu T, He T, Katusic ZS, Lee HC. Molecular mechanisms mediating inhibition of human large conductance Ca2+-activated K+ channels by high glucose. Circ Res. 2006;99:607-616. doi: 10.1161/01. RES.0000243147.41792.93.
213. Tang XD, Garcia ML, Heinemann SH, Hoshi T. Reactive oxygen species impair Slo1 BK channel function by altering cysteine-mediated calcium sensing. Nat Struct Mol Biol. 2004;11:171-178. doi: 10.1038/nsmb725.
214. Liu Y, Terata K, Chai Q, Li H, Kleinman LH, Gutterman DD. Peroxynitrite inhibits Ca2+-activated K+ channel activity in smooth muscle of human coronary arterioles. Circ Res. 2002;91:1070-1076.
215. Miller AW, Dimitropoulou C, Han G, White RE, Busija DW, Carrier GO. Epoxyeicosatrienoic acid-induced relaxation is impaired in insulin resistance. Am J Physiol Heart Circ Physiol. 2001;281:H1524-H1531.
216. Prieto D, Rivera L, Benedito S, Recio P, Villalba N, Hernández M, Garciá-Sacristán A. Ca2+-activated K+ (KCa) channels are involved in the relaxations elicited by sildenafil in penile resistance arteries. Eur J Pharmacol. 2006;531:232-237. doi: 10.1016/j. ejphar.2005.12.033.
217. Nishijima Y, Zhang DX. H2O2-induced dilation in human adipose arterioles: role of smooth muscle K+ channels. FASEB J. 2015;29:637.4.