J Korean Med Sci.  2015 Sep;30(9):1213-1225. 10.3346/jkms.2015.30.9.1213.

Endothelial Dysfunction: Clinical Implications in Cardiovascular Disease and Therapeutic Approaches

• Park KH
• Park WJ

• KMID: 2344144
• DOI: http://doi.org/10.3346/jkms.2015.30.9.1213

Abstract

Atherosclerosis is a chronic progressive vascular disease. It starts early in life, has a long asymptomatic phase, and a progression accelerated by various cardiovascular risk factors. The endothelium is an active inner layer of the blood vessel. It generates many factors that regulate vascular tone, the adhesion of circulating blood cells, smooth muscle proliferation, and inflammation, which are the key mechanisms of atherosclerosis and can contribute to the development of cardiovascular events. There is growing evidence that functional impairment of the endothelium is one of the first recognizable signs of development of atherosclerosis and is present long before the occurrence of atherosclerotic cardiovascular disease. Therefore, understanding the endothelium's central role provides not only insights into pathophysiology, but also a possible clinical opportunity to detect early disease, stratify cardiovascular risk, and assess response to treatments. In the present review, we will discuss the clinical implications of endothelial function as well as the therapeutic issues for endothelial dysfunction in cardiovascular disease as primary and secondary endothelial therapy.

Keyword

Endothelium; Atherosclerosis; Cardiovascular Disease

MeSH Terms

Animals
Atherosclerosis/*drug therapy/*immunology
Cytokines/*immunology
Endothelium, Vascular/*immunology
Humans
*Models, Immunological
Muscle, Smooth, Vascular/*immunology
Cytokines

Figure

• 

  Fig. 1 An overview of the effects of vascular endothelial factors on the function of vascular smooth muscle and circulating blood cells. In the healthy endothelium, the eNOS is responsible for most of the vascular NO production. However, eNOS becomes a potential ROS generator when in the pathological uncoupled state, due to various oxidative stresses. ACE, angiotensin-converting enzyme; Ach, acetylcholine; AT-I, angiotensin I; AT-II, angiotensin II; AT1, angiotensin 1 receptor; BH4, tetrahydrobiopterin; BK, bradykinin; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; ECE, endothelin converting enzyme; eNOS, endothelial nitric oxide synthase; EDHF, endothelium derived hyperpolarizing factor; ETA and ETB, endothelin A and B receptors; ET-1, endothelin-1; L-Arg, L-arginine; L-Cit, L-citrulline; M, muscarinic receptor; O2-, superoxide anion; ONOO-, peroxynitrite; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOX, nicotinamide adenine dinucleotide phosphate oxidase; PGH2, prostaglandin H2; PGI2, prostaglandin I2; ROS, reactive oxygen species; S1B, serotonin receptor; TP, thromboxane prostanoid receptor; TXA2, thromboxane; 5-HT, serotonin; Θ, inhibition; ⊕, stimulation.

• 

  Fig. 2 Progression from risk factors to atherosclerosis and cardiovascular disease mediated by oxidative stress and endothelial dysfunction. The early detection of endothelial dysfunction is a critical point in the prevention of atherosclerosis and cardiovascular disease because this dysfunction could be an initial reversible step in the process of atherosclerosis.

• 

  Fig. 3 Therapeutic approaches to endothelial dysfunction. Endothelial therapy can be achieved with primary endothelial therapy for prevention of healthy endothelial function by controlling cardiovascular risk factors and secondary endothelial therapy for to improve dysfunctional endothelial homeostasis by treating underlying cardiovascular risk factors and cardiovascular disease. CV, cardiovascular; PAOD, peripheral arterial occlusive disease.

Reference

1. Barton M, Haudenschild CC. Endothelium and atherogenesis: endothelial therapy revisited. J Cardiovasc Pharmacol. 2001; 38:S23–S25.

2. Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB Sr, Gibbons R, Greenland P, Lackland DT, Levy D, O'Donnell CJ, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63:2935–2959.

3. Reriani MK, Lerman LO, Lerman A. Endothelial function as a functional expression of cardiovascular risk factors. Biomark Med. 2010; 4:351–360.

4. Poredos P. Endothelial dysfunction and cardiovascular disease. Pathophysiol Haemost Thromb. 2002; 32:274–277.

5. Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, Pumper GM, Lerman LO, Lerman A. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010; 31:1142–1148.

6. Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, Lima JA, Crouse JR, Herrington DM. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation. 2009; 120:502–509.

7. Kasprzak JD, Kłosińska M, Drozdz J. Clinical aspects of assessment of endothelial function. Pharmacol Rep. 2006; 58:33–40.

8. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003; 23:168–175.

9. Mudau M, Genis A, Lochner A, Strijdom H. Endothelial dysfunction: the early predictor of atherosclerosis. Cardiovasc J Afr. 2012; 23:222–231.

10. Tousoulis D, Simopoulou C, Papageorgiou N, Oikonomou E, Hatzis G, Siasos G, Tsiamis E, Stefanadis C. Endothelial dysfunction in conduit arteries and in microcirculation. Novel therapeutic approaches. Pharmacol Ther. 2014; 144:253–267.

11. Gutiérrez E, Flammer AJ, Lerman LO, Elizaga J, Lerman A, Fernández-Avilés F. Endothelial dysfunction over the course of coronary artery disease. Eur Heart J. 2013; 34:3175–3181.

12. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007; 115:1285–1295.

13. Yang G, Lucas R, Caldwell R, Yao L, Romero MJ, Caldwell RW. Novel mechanisms of endothelial dysfunction in diabetes. J Cardiovasc Dis Res. 2010; 1:59–63.

14. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105:1135–1143.

15. Förstermann U, Münzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006; 113:1708–1714.

16. Karbach S, Wenzel P, Waisman A, Munzel T, Daiber A. eNOS uncoupling in cardiovascular diseases--the role of oxidative stress and inflammation. Curr Pharm Des. 2014; 20:3579–3594.

17. Torzewski M, Rist C, Mortensen RF, Zwaka TP, Bienek M, Waltenberger J, Koenig W, Schmitz G, Hombach V, Torzewski J. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol. 2000; 20:2094–2099.

18. Li L, Roumeliotis N, Sawamura T, Renier G. C-reactive protein enhances LOX-1 expression in human aortic endothelial cells: relevance of LOX-1 to C-reactive protein-induced endothelial dysfunction. Circ Res. 2004; 95:877–883.

19. Barton M. Prevention and endothelial therapy of coronary artery disease. Curr Opin Pharmacol. 2013; 13:226–241.

20. Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001; 89:763–771.

21. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999; 340:115–126.

22. Epstein SE, Zhu J, Burnett MS, Zhou YF, Vercellotti G, Hajjar D. Infection and atherosclerosis: potential roles of pathogen burden and molecular mimicry. Arterioscler Thromb Vasc Biol. 2000; 20:1417–1420.

23. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997; 350:430–436.

24. Grabczewska Z, Nartowicz E, Kubica J, Rość D. Endothelial function parameters in patients with unstable angina and infection with Helicobacter pylori and Chlamydia pneumoniae. Eur J Intern Med. 2006; 17:339–342.

25. Prasad A, Zhu J, Halcox JP, Waclawiw MA, Epstein SE, Quyyumi AA. Predisposition to atherosclerosis by infections: role of endothelial dysfunction. Circulation. 2002; 106:184–190.

26. Kassi E, Adamopoulos C, Basdra EK, Papavassiliou AG. Role of vitamin D in atherosclerosis. Circulation. 2013; 128:2517–2531.

27. Oz F, Cizgici AY, Oflaz H, Elitok A, Karaayvaz EB, Mercanoglu F, Bugra Z, Omer B, Adalet K, Oncul A. Impact of vitamin D insufficiency on the epicardial coronary flow velocity and endothelial function. Coron Artery Dis. 2013; 24:392–397.

28. Hirata M, Serizawa K, Aizawa K, Yogo K, Tashiro Y, Takeda S, Moriguchi Y, Endo K, Fukagawa M. 22-Oxacalcitriol prevents progression of endothelial dysfunction through antioxidative effects in rats with type 2 diabetes and early-stage nephropathy. Nephrol Dial Transplant. 2013; 28:1166–1174.

29. Andreou I, Antoniadis AP, Shishido K, Papafaklis MI, Koskinas KC, Chatzizisis YS, Coskun AU, Edelman ER, Feldman CL, Stone PH. How do we prevent the vulnerable atherosclerotic plaque from rupturing? Insights from in vivo assessments of plaque, vascular remodeling, and local endothelial shear stress. J Cardiovasc Pharmacol Ther. 2015; 20:261–275.

30. Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR, Garcia-Cardea G. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci. 2000; 902:230–239. discussion 9-40

31. Pahakis MY, Kosky JR, Dull RO, Tarbell JM. The role of endothelial glycocalyx components in mechanotransduction of fluid shear stress. Biochem Biophys Res Commun. 2007; 355:228–233.

32. White SJ, Hayes EM, Lehoux S, Jeremy JY, Horrevoets AJ, Newby AC. Characterization of the differential response of endothelial cells exposed to normal and elevated laminar shear stress. J Cell Physiol. 2011; 226:2841–2848.

33. Thijssen DH, Dawson EA, Black MA, Hopman MT, Cable NT, Green DJ. Brachial artery blood flow responses to different modalities of lower limb exercise. Med Sci Sports Exerc. 2009; 41:1072–1079.

34. Fukumoto Y, Hiro T, Fujii T, Hashimoto G, Fujimura T, Yamada J, Okamura T, Matsuzaki M. Localized elevation of shear stress is related to coronary plaque rupture: a 3-dimensional intravascular ultrasound study with in-vivo color mapping of shear stress distribution. J Am Coll Cardiol. 2008; 51:645–650.

35. Reddy KG, Nair RN, Sheehan HM, Hodgson JM. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol. 1994; 23:833–843.

36. Avogaro A, de Kreutzenberg SV, Fadini G. Endothelial dysfunction: causes and consequences in patients with diabetes mellitus. Diabetes Res Clin Pract. 2008; 82:S94–S101.

37. 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.

38. Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation. 1993; 88:2510–2516.

39. Hsueh WA, Lyon CJ, Quiñones MJ. Insulin resistance and the endothelium. Am J Med. 2004; 117:109–117.

40. Soldatos G, Cooper ME, Jandeleit-Dahm KA. Advanced-glycation end products in insulin-resistant states. Curr Hypertens Rep. 2005; 7:96–102.

41. Mineo C, Deguchi H, Griffin JH, Shaul PW. Endothelial and antithrombotic actions of HDL. Circ Res. 2006; 98:1352–1364.

42. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991; 338:1546–1550.

43. Antoniades C, Shirodaria C, Leeson P, Antonopoulos A, Warrick N, Van-Assche T, Cunnington C, Tousoulis D, Pillai R, Ratnatunga C, et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis. Eur Heart J. 2009; 30:1142–1150.

44. Vanhoutte PM, Feletou M, Taddei S. Endothelium-dependent contractions in hypertension. Br J Pharmacol. 2005; 144:449–458.

45. Tang EH, Vanhoutte PM. Endothelial dysfunction: a strategic target in the treatment of hypertension? Pflugers Arch. 2010; 459:995–1004.

46. Harrison DG, Marvar PJ, Titze JM. Vascular inflammatory cells in hypertension. Front Physiol. 2012; 3:128.

47. Burke A, Fitzgerald GA. Oxidative stress and smoking-induced vascular injury. Prog Cardiovasc Dis. 2003; 46:79–90.

48. Casey RG, Joyce M, Roche-Nagle G, Cox D, Bouchier-Hayes DJ. Young male smokers have altered platelets and endothelium that precedes atherosclerosis. J Surg Res. 2004; 116:227–233.

49. Spieker LE, Sudano I, Hürlimann D, Lerch PG, Lang MG, Binggeli C, Corti R, Ruschitzka F, Lüscher TF, Noll G. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation. 2002; 105:1399–1402.

50. Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res. 2005; 66:286–294.

51. Smith AR, Visioli F, Hagen TM. Plasma membrane-associated endothelial nitric oxide synthase and activity in aging rat aortic vascular endothelia markedly decline with age. Arch Biochem Biophys. 2006; 454:100–105.

52. Herrera MD, Mingorance C, Rodriguez-Rodriguez R, Alvarez de Sotomayor M. Endothelial dysfunction and aging: an update. Ageing Res Rev. 2010; 9:142–152.

53. Poirier P, Eckel RH. Obesity and cardiovascular disease. Curr Atheroscler Rep. 2002; 4:448–453.

54. Cardillo C, Campia U, Iantorno M, Panza JA. Enhanced vascular activity of endogenous endothelin-1 in obese hypertensive patients. Hypertension. 2004; 43:36–40.

55. Traupe T, Lang M, Goettsch W, Münter K, Morawietz H, Vetter W, Barton M. Obesity increases prostanoid-mediated vasoconstriction and vascular thromboxane receptor gene expression. J Hypertens. 2002; 20:2239–2245.

56. Campia U, Tesauro M, Cardillo C. Human obesity and endothelium-dependent responsiveness. Br J Pharmacol. 2012; 165:561–573.

57. Barton M. Childhood obesity: a life-long health risk. Acta Pharmacol Sin. 2012; 33:189–193.

58. McLenachan JM, Williams JK, Fish RD, Ganz P, Selwyn AP. Loss of flow-mediated endothelium-dependent dilation occurs early in the development of atherosclerosis. Circulation. 1991; 84:1273–1278.

59. Matsuzawa Y, Lerman A. Endothelial dysfunction and coronary artery disease: assessment, prognosis, and treatment. Coron Artery Dis. 2014; 25:713–724.

60. Hollenberg SM, Tamburro P, Johnson MR, Burns DE, Spokas D, Costanzo MR, Parrillo JE, Klein LW. Simultaneous intracoronary ultrasound and Doppler flow studies distinguish flow-mediated from receptor-mediated endothelial responses. Catheter Cardiovasc Interv. 1999; 46:282–288.

61. Ghiadoni L, Versari D, Giannarelli C, Faita F, Taddei S. Non-invasive diagnostic tools for investigating endothelial dysfunction. Curr Pharm Des. 2008; 14:3715–3722.

62. Landim MB, Casella Filho A, Chagas AC. Asymmetric dimethylarginine (ADMA) and endothelial dysfunction: implications for atherogenesis. Clinics (Sao Paulo). 2009; 64:471–478.

63. Böger RH, Vallance P, Cooke JP. Asymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase. Atheroscler Suppl. 2003; 4:1–3.

64. Lekakis J, Abraham P, Balbarini A, Blann A, Boulanger CM, Cockcroft J, Cosentino F, Deanfield J, Gallino A, Ikonomidis I, et al. Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation. Eur J Cardiovasc Prev Rehabil. 2011; 18:775–789.

65. Bove K, Neumann P, Gertzberg N, Johnson A. Role of ecNOS-derived NO in mediating TNF-induced endothelial barrier dysfunction. Am J Physiol Lung Cell Mol Physiol. 2001; 280:L914–L922.

66. Rassaf T, Feelisch M, Kelm M. Circulating NO pool: assessment of nitrite and nitroso species in blood and tissues. Free Radic Biol Med. 2004; 36:413–422.

67. Yoshinaga K, Manabe O, Tamaki N. Assessment of coronary endothelial function using PET. J Nucl Cardiol. 2011; 18:486–500.

68. Kido T, Kurata A, Higashino H, Inoue Y, Kanza RE, Okayama H, Higaki J, Murase K, Mochizuki T. Quantification of regional myocardial blood flow using first-pass multidetector-row computed tomography and adenosine triphosphate in coronary artery disease. Circ J. 2008; 72:1086–1091.

69. Salerno M, Beller GA. Noninvasive assessment of myocardial perfusion. Circ Cardiovasc Imaging. 2009; 2:412–424.

70. Iantorno M, Campia U, Di Daniele N, Nistico S, Forleo GB, Cardillo C, Tesauro M. Obesity, inflammation and endothelial dysfunction. J Biol Regul Homeost Agents. 2014; 28:169–176.

71. Hundley WG, Lange RA, Clarke GD, Meshack BM, Payne J, Landau C, McColl R, Sayad DE, Willett DL, Willard JE, et al. Assessment of coronary arterial flow and flow reserve in humans with magnetic resonance imaging. Circulation. 1996; 93:1502–1508.

72. Hays AG, Hirsch GA, Kelle S, Gerstenblith G, Weiss RG, Stuber M. Non-invasive visualization of coronary artery endothelial function in healthy subjects and in patients with coronary artery disease. J Am Coll Cardiol. 2010; 56:1657–1665.

73. Barton M. Obesity and aging: determinants of endothelial cell dysfunction and atherosclerosis. Pflugers Arch. 2010; 460:825–837.

74. Félétou M, Vanhoutte PM. Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol. 2006; 291:H985–H1002.

75. Traupe T, Ortmann J, Münter K, Barton M. Endothelial therapy of atherosclerosis and its risk factors. Curr Vasc Pharmacol. 2003; 1:111–121.

76. Higashi Y, Yoshizumi M. Exercise and endothelial function: role of endothelium-derived nitric oxide and oxidative stress in healthy subjects and hypertensive patients. Pharmacol Ther. 2004; 102:87–96.

77. Wienbergen H, Hambrecht R. Physical exercise and its effects on coronary artery disease. Curr Opin Pharmacol. 2013; 13:218–225.

78. Hambrecht R, Hilbrich L, Erbs S, Gielen S, Fiehn E, Schoene N, Schuler G. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. J Am Coll Cardiol. 2000; 35:706–713.

79. Bigornia SJ, Mott MM, Hess DT, Apovian CM, McDonnell ME, Duess MA, Kluge MA, Fiscale AJ, Vita JA, Gokce N. Long-term successful weight loss improves vascular endothelial function in severely obese individuals. Obesity (Silver Spring). 2010; 18:754–759.

80. Gokce N, Vita JA, McDonnell M, Forse AR, Istfan N, Stoeckl M, Lipinska I, Keaney JF Jr, Apovian CM. Effect of medical and surgical weight loss on endothelial vasomotor function in obese patients. Am J Cardiol. 2005; 95:266–268.

81. Messner B, Bernhard D. Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol. 2014; 34:509–515.

82. Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993; 88:2149–2155.

83. Johnson HM, Gossett LK, Piper ME, Aeschlimann SE, Korcarz CE, Baker TB, Fiore MC, Stein JH. Effects of smoking and smoking cessation on endothelial function: 1-year outcomes from a randomized clinical trial. J Am Coll Cardiol. 2010; 55:1988–1995.

84. Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med. 1996; 334:150–154.

85. Davis N, Katz S, Wylie-Rosett J. The effect of diet on endothelial function. Cardiol Rev. 2007; 15:62–66.

86. Lopez-Garcia E, Schulze MB, Fung TT, Meigs JB, Rifai N, Manson JE, Hu FB. Major dietary patterns are related to plasma concentrations of markers of inflammation and endothelial dysfunction. Am J Clin Nutr. 2004; 80:1029–1035.

87. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999; 99:779–785.

88. Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, D'Armiento M, D'Andrea F, Giugliano D. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004; 292:1440–1446.

89. Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol. 2002; 40:505–510.

90. Kitta Y, Obata JE, Nakamura T, Hirano M, Kodama Y, Fujioka D, Saito Y, Kawabata K, Sano K, Kobayashi T, et al. Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. J Am Coll Cardiol. 2009; 53:323–330.

91. Kinlay S, Libby P, Ganz P. Endothelial function and coronary artery disease. Curr Opin Lipidol. 2001; 12:383–389.

92. Erbs S, Höllriegel R, Linke A, Beck EB, Adams V, Gielen S, Möbius-Winkler S, Sandri M, Kränkel N, Hambrecht R, et al. Exercise training in patients with advanced chronic heart failure (NYHA IIIb) promotes restoration of peripheral vasomotor function, induction of endogenous regeneration, and improvement of left ventricular function. Circ Heart Fail. 2010; 3:486–494.

93. Thai H, Guarraia D, Johnson N, Goldman S, Gaballa MA. Valsartan therapy in heart failure after myocardial infarction: the role of endothelial dependent vasorelaxation. J Cardiovasc Pharmacol. 2007; 50:703–707.

94. Malyszko J. Mechanism of endothelial dysfunction in chronic kidney disease. Clin Chim Acta. 2010; 411:1412–1420.

95. Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med. 1995; 332:488–493.

96. Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyond lipid lowering--are they clinically relevant? Eur Heart J. 2003; 24:225–248.

97. Kirmizis D, Papagianni A, Dogrammatzi F, Skoura L, Belechri AM, Alexopoulos E, Efstratiadis G, Memmos D. Effects of simvastatin on markers of inflammation, oxidative stress and endothelial cell apoptosis in patients on chronic hemodialysis. J Atheroscler Thromb. 2010; 17:1256–1265.

98. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998; 97:1129–1135.

99. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004; 109:III27–III32.

100. Ling MC, Ruddy TD, deKemp RA, Ukkonen H, Duchesne L, Higginson L, Williams KA, McPherson R, Beanlands R. Early effects of statin therapy on endothelial function and microvascular reactivity in patients with coronary artery disease. Am Heart J. 2005; 149:1137.

101. Dupuis J, Tardif JC, Rouleau JL, Ricci J, Arnold M, Lonn E, Roux R, Title LM, Amyot R, Bonafede N, et al. Intensity of lipid lowering with statins and brachial artery vascular endothelium reactivity after acute coronary syndromes (from the BRAVER trial). Am J Cardiol. 2005; 96:1207–1213.

102. Reriani MK, Dunlay SM, Gupta B, West CP, Rihal CS, Lerman LO, Lerman A. Effects of statins on coronary and peripheral endothelial function in humans: a systematic review and meta-analysis of randomized controlled trials. Eur J Cardiovasc Prev Rehabil. 2011; 18:704–716.

103. Watanabe T, Barker TA, Berk BC. Angiotensin II and the endothelium: diverse signals and effects. Hypertension. 2005; 45:163–169.

104. Sola S, Mir MQ, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S, Khan BV. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation. 2005; 111:343–348.

105. Rajagopalan S, Harrison DG. Reversing endothelial dysfunction with ACE inhibitors. A new trend. Circulation. 1996; 94:240–243.

106. Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Lüscher TF, Klibaner MI, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996; 94:258–265.

107. Shahin Y, Khan JA, Samuel N, Chetter I. Angiotensin converting enzyme inhibitors effect on endothelial dysfunction: a meta-analysis of randomised controlled trials. Atherosclerosis. 2011; 216:7–16.

108. Wood JM, Cumin F, Maibaum J. Pharmacology of renin inhibitors and their application to the treatment of hypertension. Pharmacol Ther. 1994; 61:325–344.

109. Stanton A, Jensen C, Nussberger J, O'Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension. 2003; 42:1137–1143.

110. Imanishi T, Tsujioka H, Ikejima H, Kuroi A, Takarada S, Kitabata H, Tanimoto T, Muragaki Y, Mochizuki S, Goto M, et al. Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes. Hypertension. 2008; 52:563–572.

111. Chou CL, Pang CY, Lee TJ, Fang TC. Direct renin inhibitor prevents and ameliorates insulin resistance, aortic endothelial dysfunction and vascular remodeling in fructose-fed hypertensive rats. Hypertens Res. 2013; 36:123–128.

112. Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ, Webb DJ. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation. 1998; 97:752–756.

113. Lerman A, Holmes DR Jr, Bell MR, Garratt KN, Nishimura RA, Burnett JC Jr. Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. Circulation. 1995; 92:2426–2431.

114. Halcox JP, Nour KR, Zalos G, Quyyumi AA. Coronary vasodilation and improvement in endothelial dysfunction with endothelin ET(A) receptor blockade. Circ Res. 2001; 89:969–976.

115. Khan MU, Zhao W, Zhao T, Al Darazi F, Ahokas RA, Sun Y, Bhattacharya SK, Gerling IC, Weber KT. Nebivolol: a multifaceted antioxidant and cardioprotectant in hypertensive heart disease. J Cardiovasc Pharmacol. 2013; 62:445–451.

116. Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, Jankowski M, Martyniec L, Angielski S, Malinski T. Third-generation beta-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation. 2003; 107:2747–2752.

117. Bank AJ, Kelly AS, Thelen AM, Kaiser DR, Gonzalez-Campoy JM. Effects of carvedilol versus metoprolol on endothelial function and oxidative stress in patients with type 2 diabetes mellitus. Am J Hypertens. 2007; 20:777–783.

118. Ruiz-Larrea B, Leal A, Martin C, Martinez R, Lacort M. Effects of estrogens on the redox chemistry of iron: a possible mechanism of the anti-oxidant action of estrogens. Steroids. 1995; 60:780–783.

119. Collins P, Shay J, Jiang C, Moss J. Nitric oxide accounts for dose-dependent estrogen-mediated coronary relaxation after acute estrogen withdrawal. Circulation. 1994; 90:1964–1968.

120. Sumino H, Ichikawa S, Kasama S, Takahashi T, Sakamoto H, Koizumi A, Kanai H, Araki Y, Itoh T, Iwasaki T, et al. Effects of raloxifene on brachial arterial endothelial function, carotid wall thickness, and arterial stiffness in osteoporotic postmenopausal women. Int Heart J. 2010; 51:60–67.