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The role of nitric oxide in early atherosclerosis

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Abstract

Atherosclerosis is a chronic inflammatory disease that begins in early life. Atherosclerotic lesions are often detectable in conduit arteries during childhood, and fatty streaks may even arise during fetal development. Endothelial dysfunction, characterized by reduced bioavailability of nitric oxide (NO), promotes the initiation and development of atherosclerotic lesions and contributes to the pathogenesis of plaque instability and thrombosis, the hallmark of acute complications such as myocardial infarction. Exposure of the vascular endothelium of young subjects to conventional as well as novel risk factors for atherosclerosis typically leads to the development of endothelial dysfunction, which can be detected reliably in vivo using noninvasive methods such as ultrasound assessment of brachial artery flow-mediated vasodilatation. Such techniques have contributed greatly to our mechanistic understanding of clinical atherogenesis and may play an important role in the development of strategies for detecting and treating young subjects with increased atherosclerotic risk. In this review, we describe the techniques available for the clinical assessment of NO-dependent vascular function. We also review the determinants of early endothelial dysfunction and describe strategies operating at the level of the endothelium that may be appropriate for risk modification in the young.

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References

  1. Enos WF, Holms RH, Beyer J (1953) Coronary disease among United States soldiers killed in action in Korea; preliminary report. J Am Med Assoc 152:1090–1093

    PubMed  CAS  Google Scholar 

  2. Stary HC (1989) Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis 9(1 Suppl):I19–I32

    PubMed  CAS  Google Scholar 

  3. Napoli C, D'Armiento FP, Mancini FP, Postiglione A, Witztum JL, Palumbo G, Palinski W (1997) Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 100:2680–2690

    PubMed  CAS  Google Scholar 

  4. Napoli C, Witztum JL, de Nigris F, Palumbo G, D'Armiento FP, Palinski W (1999) Intracranial arteries of human fetuses are more resistant to hypercholesterolemia-induced fatty streak formation than extracranial arteries. Circulation 99:2003–2010

    PubMed  CAS  Google Scholar 

  5. Napoli C, Glass CK, Witztum JL, Deutsch R, D'Armiento FP, Palinski W (1999) Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 354:1234–1241

    PubMed  CAS  Google Scholar 

  6. Palinski W, Napoli C (1999) Pathophysiological events during pregnancy influence the development of atherosclerosis in humans. Trends Cardiovasc Med 9:205–214

    PubMed  CAS  Google Scholar 

  7. Boren J, Olin K, Lee I, Chait A, Wight TN, Innerarity TL (1998) Identification of the principal proteoglycan-binding site in LDL. A single-point mutation in apo-B100 severely affects proteoglycan interaction without affecting LDL receptor binding. J Clin Invest 101:2658–2664

    PubMed  CAS  Google Scholar 

  8. Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA (1998) Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 338:1650–1656

    PubMed  CAS  Google Scholar 

  9. Li S, Chen W, Srinivasan SR, Bond MG, Tang R, Urbina EM, Berenson GS (2003) Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA 290:2271–2276

    PubMed  CAS  Google Scholar 

  10. Oren A, Vos LE, Uiterwaal CS, Grobbee DE, Bots ML (2003) Cardiovascular risk factors and increased carotid intima-media thickness in healthy young adults: the Atherosclerosis Risk in Young Adults (ARYA) Study. Arch Intern Med 163:1787–1792

    PubMed  Google Scholar 

  11. Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376

    PubMed  CAS  Google Scholar 

  12. Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526

    PubMed  CAS  Google Scholar 

  13. Palmer RM, Ashton DS, Moncada S (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333:664–666

    PubMed  CAS  Google Scholar 

  14. Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012

    PubMed  CAS  Google Scholar 

  15. Palmer RM, Moncada S (1989) A novel citrulline-forming enzyme implicated in the formation of nitric oxide by vascular endothelial cells. Biochem Biophys Res Commun 158:348–352

    PubMed  CAS  Google Scholar 

  16. Stuehr DJ, Kwon NS, Nathan CF (1990) FAD and GSH participate in macrophage synthesis of nitric oxide. Biochem Biophys Res Commun 168:558–565

    PubMed  CAS  Google Scholar 

  17. Tayeh MA, Marletta MA (1989) Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor. J Biol Chem 264:19654–19658

    PubMed  CAS  Google Scholar 

  18. Tran CT, Leiper JM, Vallance P (2003) The DDAH/ADMA/NOS pathway. Atheroscler Suppl 4:33–40

    PubMed  CAS  Google Scholar 

  19. Verma S, Anderson TJ (2002) Fundamentals of endothelial function for the clinical cardiologist. Circulation 105:546–549

    PubMed  CAS  Google Scholar 

  20. Luscher TF, Noll G (1995) The pathogenesis of cardiovascular disease: role of the endothelium as a target and mediator. Atherosclerosis 118(Suppl):S81–S90

    Article  PubMed  CAS  Google Scholar 

  21. Behrendt D, Ganz P (2002) Endothelial function. From vascular biology to clinical applications. Am J Cardiol 90:40L–48L

    PubMed  CAS  Google Scholar 

  22. Desideri G, Marinucci MC, Tomassoni G, Masci PG, Santucci A, Ferri C (2002) Vitamin E supplementation reduces plasma vascular cell adhesion molecule-1 and von Willebrand factor levels and increases nitric oxide concentrations in hypercholesterolemic patients. J Clin Endocrinol Metab 87:2940–2945

    PubMed  CAS  Google Scholar 

  23. Ferri C, Desideri G, Baldoncini R, Bellini C, De Angelis C, Mazzocchi C, Santucci A (1998) Early activation of vascular endothelium in nonobese, nondiabetic essential hypertensive patients with multiple metabolic abnormalities. Diabetes 47:660–667

    PubMed  CAS  Google Scholar 

  24. Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA (1998) CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591–594

    PubMed  CAS  Google Scholar 

  25. Schonbeck U, Libby P (2001) CD40 signaling and plaque instability. Circ Res 89:1092–1103

    PubMed  CAS  Google Scholar 

  26. Berthiaume F, Frangos JA (1992) Flow-induced prostacyclin production is mediated by a pertussis toxin-sensitive G protein. FEBS Lett 308:277–279

    PubMed  CAS  Google Scholar 

  27. Vallance P, Chan N (2001) Endothelial function and nitric oxide: clinical relevance. Heart 85:342–350

    PubMed  CAS  Google Scholar 

  28. Sorensen KE, Celermajer DS, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Thomas O, Deanfield JE (1995) Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility. Br Heart J 74:247–253

    PubMed  CAS  Google Scholar 

  29. Deanfield JE, Donald AE, Ferri C, Halcox JPJ, Halligan S, Lerman A, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Schiffrin EL, Taddei S, Webb DJ (2005) Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds. A statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens 23:7–17

    PubMed  CAS  Google Scholar 

  30. Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Menzoian JO, Vita JA (2002) Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation 105:1567–1572

    PubMed  Google Scholar 

  31. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA (2002) Prognostic value of coronary vascular endothelial dysfunction. Circulation 106:653–658

    PubMed  Google Scholar 

  32. Neunteufl T, Heher S, Katzenschlager R, Wolfl G, Kostner K, Maurer G, Weidinger F (2000) Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol 86:207–210

    PubMed  CAS  Google Scholar 

  33. Sorensen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE (1994) Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J Clin Invest 93:50–55

    Article  PubMed  CAS  Google Scholar 

  34. Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE (1994) Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol 24:1468–1474

    Article  PubMed  CAS  Google Scholar 

  35. Khan F, Elhadd TA, Greene SA, Belch JJ (2000) Impaired skin microvascular function in children, adolescents, and young adults with type 1 diabetes. Diabetes Care 23:215–220

    PubMed  CAS  Google Scholar 

  36. Mackenzie IS, Wilkinson IB, Cockcroft JR (2002) Assessment of arterial stiffness in clinical practice. QJM 95:67–74

    PubMed  CAS  Google Scholar 

  37. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE (1994) Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 24:471–476

    Article  PubMed  CAS  Google Scholar 

  38. [No authors listed] (1976) The multiple risk factor intervention trial (MRFIT). A national study of primary prevention of coronary heart disease. JAMA 235:825–827

    Google Scholar 

  39. Klag MJ, Ford DE, Mead LA, He J, Whelton PK, Liang KY, Levine DM (1993) Serum cholesterol in young men and subsequent cardiovascular disease. N Engl J Med 328:313–318

    PubMed  CAS  Google Scholar 

  40. Clarkson P, Celermajer DS, Donald AE, Sampson M, Sorensen KE, Adams M, Yue DK, Betteridge DJ, Deanfield JE (1996) Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J Am Coll Cardiol 28:573–579

    Article  PubMed  CAS  Google Scholar 

  41. Feener EP, King GL (2001) Endothelial dysfunction in diabetes mellitus: role in cardiovascular disease. Heart Fail Monit 1:74–82

    PubMed  CAS  Google Scholar 

  42. Poston L, Taylor PD (1995) Glaxo/MRS Young Investigator Prize. Endothelium-mediated vascular function in insulin-dependent diabetes mellitus. Clin Sci 88:245–255

    PubMed  CAS  Google Scholar 

  43. Tesfamariam B, Cohen RA (1992) Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 263:H321–H326

    PubMed  CAS  Google Scholar 

  44. Fard A, Tuck CH, Donis JA, Sciacca R, Di Tullio MR, Wu HD, Bryant TA, Chen NT, Torres-Tamayo M, Ramasamy R, Berglund L, Ginsberg HN, Homma S, Cannon PJ (2000) Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 20:2039–2044

    PubMed  CAS  Google Scholar 

  45. Elhadd TA, Kennedy G, Hill A, McLaren M, Newton RW, Greene SA, Belch JJ (1999) Abnormal markers of endothelial cell activation and oxidative stress in children, adolescents and young adults with type 1 diabetes with no clinical vascular disease. Diabetes Metab Res Rev 15:405–411

    PubMed  CAS  Google Scholar 

  46. Lacy F, O'Connor DT, Schmid-Schonbein GW (1998) Plasma hydrogen peroxide production in hypertensives and normotensive subjects at genetic risk of hypertension. J Hypertens 16:291–303

    PubMed  CAS  Google Scholar 

  47. Swei A, Lacy F, DeLano FA, Schmid-Schonbein GW (1997) Oxidative stress in the Dahl hypertensive rat. Hypertension 30:1628–1633

    PubMed  CAS  Google Scholar 

  48. Goonasekera CD, Dillon MJ (1998) Vascular endothelium and nitric oxide in childhood hypertension. Pediatr Nephrol 12:676–689

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  51. Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y, Strauss WE, Oates JA, Roberts LJ (1995) Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. N Engl J Med 332:1198–1203

    PubMed  CAS  Google Scholar 

  52. Singh N, Prasad S, Singer DR, MacAllister RJ (2002) Ageing is associated with impairment of nitric oxide and prostanoid dilator pathways in the human forearm. Clin Sci 102:595–600

    PubMed  CAS  Google Scholar 

  53. Taddei S, Virdis A, Ghiadoni L, Salvetti G, Bernini G, Magagna A, Salvetti A (2001) Age-related reduction of NO availability and oxidative stress in humans. Hypertension 38:274–279

    PubMed  CAS  Google Scholar 

  54. Hingorani AD, Cross J, Kharbanda RK, Mullen MJ, Bhagat K, Taylor M, Donald AE, Palacios M, Griffin GE, Deanfield JE, MacAllister RJ, Vallance P (2000) Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation 102:994–999

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  56. Ridker PM (2003) Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107:363–369

    PubMed  Google Scholar 

  57. Smieja M, Gnarpe J, Lonn E, Gnarpe H, Olsson G, Yi Q, Dzavik V, McQueen M, Yusuf S (2003) Multiple infections and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation 107:251–257

    PubMed  Google Scholar 

  58. Jarvisalo MJ, Harmoinen A, Hakanen M, Paakkunainen U, Viikari J, Hartiala J, Lehtimaki T, Simell O, Raitakari OT (2002) Elevated serum C-reactive protein levels and early arterial changes in healthy children. Arterioscler Thromb Vasc Biol 22:1323–1328

    PubMed  CAS  Google Scholar 

  59. Liuba P, Persson J, Luoma J, Yla-Herttuala S, Pesonen E (2003) Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima-media. Eur Heart J 24:515–521

    PubMed  CAS  Google Scholar 

  60. Charakida M, Donald AE, Terese M, Leary S, Halcox JPJ, Ness A, Davey Smith G, Golding J, Friberg P, Klein NJ, Deanfield JE; ALSPAC (Avon Longitudinal Study of Parents and Children) Study Team (2005) Endothelial dysfunction in childhood infection. Circulation 111:1660–1665

    PubMed  Google Scholar 

  61. Cheung YF, Brogan PA, Pilla CB, Dillon MJ, Redington AN (2002) Arterial distensibility in children and teenagers: normal evolution and the effect of childhood vasculitis. Arch Dis Child 87:348–351

    PubMed  CAS  Google Scholar 

  62. Dhillon R, Clarkson P, Donald AE, Powe AJ, Nash M, Novelli V, Dillon MJ, Deanfield JE (1996) Endothelial dysfunction late after Kawasaki disease. Circulation 94:2103–2106

    PubMed  CAS  Google Scholar 

  63. Ogden CL, Flegal KM, Carroll MD, Johnson CL (2002) Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 288:1728–1732

    PubMed  Google Scholar 

  64. Gunnell DJ, Frankel SJ, Nanchahal K, Peters TJ, Davey SG (1998) Childhood obesity and adult cardiovascular mortality: a 57-y follow-up study based on the Boyd Orr cohort. Am J Clin Nutr 67:1111–1118

    PubMed  CAS  Google Scholar 

  65. Mahoney LT, Burns TL, Stanford W, Thompson BH, Witt JD, Rost CA, Lauer RM (1996) Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine Study. J Am Coll Cardiol 27:277–284

    PubMed  CAS  Google Scholar 

  66. Must A, Jacques PF, Dallal GE, Bajema CJ, Dietz WH (1992) Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. N Engl J Med 327:1350–1355

    Article  PubMed  CAS  Google Scholar 

  67. Kannel WB (1987) Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study. Am Heart J 114:413–419

    PubMed  CAS  Google Scholar 

  68. Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, Girardet JP, Bonnet D (2001) Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study. Lancet 358:1400–1404

    PubMed  CAS  Google Scholar 

  69. Singhal A, Farooqi IS, Cole TJ, O'Rahilly S, Fewtrell M, Kattenhorn M, Lucas A, Deanfield J (2002) Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease? Circulation 106:1919–1924

    PubMed  CAS  Google Scholar 

  70. Halcox JP, Zalos G, Charakida M, Quyyumi A (2004) Obesity predicts coronary endothelial dysfunction independently of inflammation, atherosclerosis and conventional risk factors. J Am Coll Cardiol 43:485A

    Google Scholar 

  71. Clarkson P, Celermajer DS, Powe AJ, Donald AE, Henry RM, Deanfield JE (1997) Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease. Circulation 96:3378–3383

    PubMed  CAS  Google Scholar 

  72. Leeson P, Thorne S, Donald A, Mullen M, Clarkson P, Deanfield J (1997) Non-invasive measurement of endothelial function: effect on brachial artery dilatation of graded endothelial dependent and independent stimuli. Heart 78:22–27

    PubMed  CAS  Google Scholar 

  73. Savvidou MD, Vallance PJ, Nicolaides KH, Hingorani AD (2001) Endothelial nitric oxide synthase gene polymorphism and maternal vascular adaptation to pregnancy. Hypertension 38:1289–1293

    PubMed  CAS  Google Scholar 

  74. Golding J, Pembrey M, Jones R (2001) ALSPAC-the Avon Longitudinal Study of Parents and Children. I. Study methodology. Paediatr Perinat Epidemiol 15:74–87

    PubMed  CAS  Google Scholar 

  75. Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ (2000) Early growth, adult income, and risk of stroke. Stroke 31:869–874

    PubMed  CAS  Google Scholar 

  76. Leon DA, Lithell HO, Vagero D, Koupilova I, Mohsen R, Berglund L, Lithell UB, McKeigue PM (1998) Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915–29. Br Med J 317:241–245

    CAS  Google Scholar 

  77. Martyn CN, Barker DJ, Osmond C (1996) Mothers' pelvic size, fetal growth, and death from stroke and coronary heart disease in men in the UK. Lancet 348:1264–1268

    PubMed  CAS  Google Scholar 

  78. Goodfellow J, Bellamy MF, Gorman ST, Brownlee M, Ramsey MW, Lewis MJ, Davies DP, Henderson AH (1998) Endothelial function is impaired in fit young adults of low birth weight. Cardiovasc Res 40:600–606

    PubMed  CAS  Google Scholar 

  79. Leeson CP, Kattenhorn M, Morley R, Lucas A, Deanfield JE (2001) Impact of low birth weight and cardiovascular risk factors on endothelial function in early adult life. Circulation 103:1264–1268

    PubMed  CAS  Google Scholar 

  80. Martin H, Hu J, Gennser G, Norman M (2000) Impaired endothelial function and increased carotid stiffness in 9-year-old children with low birthweight. Circulation 102:2739–2744

    PubMed  CAS  Google Scholar 

  81. Martin H, Gazelius B, Norman M (2000) Impaired acetylcholine-induced vascular relaxation in low birth weight infants: implications for adult hypertension? Pediatr Res 47:457–462

    PubMed  CAS  Google Scholar 

  82. McAllister AS, Atkinson AB, Johnston GD, McCance DR (1999) Relationship of endothelial function to birth weight in humans. Diabetes Care 22:2061–2066

    PubMed  CAS  Google Scholar 

  83. Singhal A, Fewtrell M, Cole TJ, Lucas A (2003) Low nutrient intake and early growth for later insulin resistance in adolescents born preterm. Lancet 361:1089–1097

    PubMed  CAS  Google Scholar 

  84. Lithell HO, McKeigue PM, Berglund L, Mohsen R, Lithell UB, Leon DA (1996) Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50–60 years. Br Med J 312:406–410

    CAS  Google Scholar 

  85. Mi J, Law C, Zhang KL, Osmond C, Stein C, Barker D (2000) Effects of infant birthweight and maternal body mass index in pregnancy on components of the insulin resistance syndrome in China. Ann Intern Med 132:253–260

    PubMed  CAS  Google Scholar 

  86. Valdez R, Athens MA, Thompson GH, Bradshaw BS, Stern MP (1994) Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia 37:624–631

    PubMed  CAS  Google Scholar 

  87. Huxley RR, Shiell AW, Law CM (2000) The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens 18:815–831

    PubMed  CAS  Google Scholar 

  88. Martyn CN, Gale CR, Jespersen S, Sherriff SB (1998) Impaired fetal growth and atherosclerosis of carotid and peripheral arteries. Lancet 352:173–178

    PubMed  CAS  Google Scholar 

  89. Celermajer DS, Sorensen K, Ryalls M, Robinson J, Thomas O, Leonard JV, Deanfield JE (1993) Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol 22:854–858

    Article  PubMed  CAS  Google Scholar 

  90. Ghiadoni L, Donald AE, Cropley M, Mullen MJ, Oakley G, Taylor M, O'Connor G, Betteridge J, Klein N, Steptoe A, Deanfield JE (2000) Mental stress induces transient endothelial dysfunction in humans. Circulation 102:2473–2478

    PubMed  CAS  Google Scholar 

  91. Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S (2001) Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 103:1933–1935

    PubMed  CAS  Google Scholar 

  92. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E (1999) Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 100:230–235

    PubMed  CAS  Google Scholar 

  93. Diaz MN, Frei B, Vita JA, Keaney JF Jr (1997) Antioxidants and atherosclerotic heart disease. N Engl J Med 337:408–416

    PubMed  CAS  Google Scholar 

  94. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. The heart outcomes prevention evaluation study investigators. N Engl J Med 342:154–160

    PubMed  CAS  Google Scholar 

  95. Munzel T, Keaney JF Jr (2001) Are ACE inhibitors a “magic bullet” against oxidative stress? Circulation 104:1571–1574

    PubMed  CAS  Google Scholar 

  96. Hambrecht R, Wolf A, Gielen S, Linke A, Hofer J, Erbs S, Schoene N, Schuler G (2000) Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med 342:454–460

    PubMed  CAS  Google Scholar 

  97. Shephard RJ, Balady GJ (1999) Exercise as cardiovascular therapy. Circulation 99:963–972

    PubMed  CAS  Google Scholar 

  98. Szmitko PE, Fedak PW, Weisel RD, Stewart DJ, Kutryk MJ, Verma S (2003) Endothelial progenitor cells: new hope for a broken heart. Circulation 107:3093–3100

    PubMed  Google Scholar 

  99. Iwaguro H, Yamaguchi J, Kalka C, Murasawa S, Masuda H, Hayashi S, Silver M, Li T, Isner JM, Asahara T (2002) Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation 105:732–738

    PubMed  CAS  Google Scholar 

  100. Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S (2000) Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 95:952–958

    PubMed  CAS  Google Scholar 

  101. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348:593–600

    PubMed  Google Scholar 

  102. Assmus B, Urbich C, Aicher A, Hofmann WK, Haendeler J, Rossig L, Spyridopoulos I, Zeiher AM, Dimmeler S (2003) HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ Res 92:1049–1055

    PubMed  CAS  Google Scholar 

  103. Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM (2001) HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 108:391–397

    PubMed  CAS  Google Scholar 

  104. Laufs U, Werner N, Link A, Endres M, Wassmann S, Jurgens K, Miche E, Bohm M, Nickenig G (2004) Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 109:220–226

    PubMed  CAS  Google Scholar 

  105. Llevadot J, Murasawa S, Kureishi Y, Uchida S, Masuda H, Kawamoto A, Walsh K, Isner JM, Asahara T (2001) HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest 108:399–405

    PubMed  CAS  Google Scholar 

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Charakida, M., Deanfield, J.E. & Halcox, J.P.J. The role of nitric oxide in early atherosclerosis. Eur J Clin Pharmacol 62 (Suppl 1), 69–78 (2006). https://doi.org/10.1007/s00228-005-0007-9

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