Hostname: page-component-cd9895bd7-q99xh Total loading time: 0 Render date: 2024-12-18T07:10:38.024Z Has data issue: false hasContentIssue false
  • English
  • Français

Endothelial dysfunction: role in obesity-related disorders and the early origins of CVD

Published online by Cambridge University Press:  07 March 2007

Atul Singhal
Atul Singhal
Affiliation:
MRC Childhood Nutrition Research Centre, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Atherosclerotic CVD is the most common cause of death in the West. Yet, its pathogenesis and early development are only partially understood. Central to the early atherosclerotic process is impairment of vascular endothelial function. Endothelial dysfunction can be measured non-invasively and is evident in children before clinical manifestations of atherosclerosis in adulthood. Factors in early life, such as conventional cardiovascular risk factors, or programming by perinatal growth and nutrition strongly affect endothelial function and hence the development of atherosclerosis and CVD. For instance, low birth weight and faster growth early in infancy have a detrimental effect on vascular structure and function. Childhood obesity, a key independent risk factor for CVD, also adversely affects early vascular health. Obesity is associated with endothelial dysfunction and greater arterial stiffness from as early as the first decade of life, while weight loss is beneficial. This effect on vascular function is probably mediated in part by low-grade inflammation and insulin resistance associated with obesity or by the production by adipose tissue of cytokine-like molecules, collectively termed adipokines. A high leptin concentration, in particular, is found in obese individuals and is strongly associated with vascular changes related to early atherosclerosis. The present review focuses on the early origins of endothelial dysfunction, emphasising the role of obesity. It also considers the mechanisms by which obesity impairs endothelial function, understanding of which will be important to further scientific knowledge and to improve public health.

Keywords

Endothelial dysfunctionRole of obesityEarly origins of CVD
Type
Symposium on ‘Obesity and metabolic diseases’
Information
Proceedings of the Nutrition Society , Volume 64 , Issue 1 , February 2005 , pp. 15 - 22
Copyright
Copyright © The Nutrition Society 2005

References

Anderson, TJ, Uehata, A, Gerhard, MD, Meridith, IT, Knab, S, Delagrange, D, Lieberman, EH, Ganz, P, Creager, MA, Yeung, AC & Selwyn, AP (1995) Close relation of endothelial function in the human coronary and peripheral circulations. Journal of the American College of Cardiology 26, 1235–1241.CrossRefGoogle ScholarPubMed
Arcaro, G, Zamboni, M, Rossi, L, Turcato, E, Covi, G, Armellini, F, Bosello, O & Lechi, A (1999) Body fat distribution predicts the degree of endothelial dysfunction in uncomplicated obesity. International Journal of Obesity and Related Metabolic Disorders 23, 936–942.CrossRefGoogle ScholarPubMed
Barker, DJP, Gluckman, PD, Godfrey, KM, Harding, JE, Owen, JA & Robinson, JS (1993) Fetal nutrition and cardiovascular disease in adult life. Lancet 341, 938–941.CrossRefGoogle ScholarPubMed
Blacher, J, Asmar, R, Djane, S, London, GM & Safar, ME (1999) Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 33, 1111–1117.CrossRefGoogle ScholarPubMed
Brindle, P, Emberson, J, Lampe, F, Walker, M, Whincup, P, Fahey, T & Ebrahim, S (2003) Predictive accuracy of the Framingham coronary risk score in British men: prospective cohort study. British Medical Journal 327, 1267–1273.Google Scholar
Brook, RD, Bard, RL, Glazewski, L, Kehrer, C, Bodary, PF, Eitzman, DL & Rajagopalan, S (2004) Effect of short-term weight loss on the metabolic syndrome and conduit vascular endothelial function in overweight adults. American Journal of Cardiology 93, 1012–1016.Google Scholar
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.CrossRefGoogle ScholarPubMed
Cheung, YF, Wong, KY, Lam, BCC & Tsoi, NS (2004) Relation of arterial stiffness with gestational age and birth weight. Archives of Disease in Childhood 89, 217–221.Google Scholar
Cianfarani, S, Germani, D & Branca, F (1999) Low birthweight and adult insulin resistance: the ‘catch-up growth’ hypothesis. Archives of Disease in Childhood 81, F71–F73.CrossRefGoogle ScholarPubMed
Clarkson, P, Celermajer, DS, Donald, AE, Sampson, M, Sorensen, KE, Adams, M, Yue, DK, Betteridge, J & Deanfield, JE (1996) Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. Journal of the American College of Cardiology 28, 573–579.Google Scholar
Frankel, S, Elwood, P, Sweetnam, P, Yarnell, J & Davey, G (1996) Birthweight, body mass index in middle age and incident coronary heart disease. Lancet 348, 1478–1480.Google Scholar
Furchgott, RF & Zawadzki, JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373–376.CrossRefGoogle ScholarPubMed
Hahn, P (1984) Effect of litter size on plasma cholesterol and insulin and some liver and adipose tissue enzymes in adult rodents. Journal of Nutrition 114, 1231–1234.Google Scholar
Hermann, TS, Rask-Madsen, C, Ihlemann, N, Dominguez, H, Jensen, CB, Storgaard, H, Vaag, AA, Kober, L, Torp-Pedersen, C (2003) Normal insulin-stimulated endothelial function and impaired insulin-stimulated muscle glucose uptake in young adults with low birth weight. Journal of Clinical Endocrinology and Metabolism 88, 1252–1257.Google Scholar
Hirai, T, Sasayama, S, Kawasaki, T, Shin-ichi, Y (1989) Stiffness of systemic arteries in patients with myocardial infarction: a non-invasive method to predict severity of coronary atherosclerosis. Circulation 80, 78–86.Google Scholar
Klag, MJ, Ford, DE, Mead, LA, He, J, Whelton, PK, Liang, K & Levine, DM (1993) Serum cholesterol in young men and subsequent cardiovascular disease. New England Journal of Medicine 328, 313–318.Google Scholar
Konstantinides, S, Schafer, K, Koschnick, S & Loskutoff, DJ (2001) Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. Journal of Clinical Investigation 108, 1533–1540.Google Scholar
Kumada, M, Kihara, S, Sumitsuji, S, Kawamoto, T, Matsumoto, S, Ouchi, N et al. (2003) Association of hypoadiponectinemia with coronary artery disease in men. Arteriosclerosis, Thrombosis and Vascular Biology 23, 85–89.CrossRefGoogle ScholarPubMed
Kuvin, JT & Karas, RH (2003) Clinical utility of endothelial function testing; ready for prime time. Circulation 107, 3243–3247.Google Scholar
Lamont, D, Parker, L, White, M, Unwin, N, Bennett, SMA, Cohen, M, Richardson, D, Dickinson, HO, Adamson, A, Alberti, KGMM & Craft, AW (2000) Risk of cardiovascular disease measured by carotid intima-media thickness at age 49–51: life course study. British Medical Journal 320, 273–278.CrossRefGoogle Scholar
Leeson, CPM, 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.Google Scholar
Leeson, CPM, Whincup, PH, Cook, DG, Donald, AE, Papacosta, O, Lucas, A & Deanfield, JE (1997) Flow-mediated dilation in 9- to 11-year-old children. The influence of intrauterine and childhood factors. Circulation 96, 2233–2238.CrossRefGoogle ScholarPubMed
Leeson, CPM, Whincup, PH, Cook, DG, Mullen, MJ, Donald, AE, Seymour, CA & Deanfield, JE (2000) Cholesterol and arterial distensibility in the first decade of life: a population-based study. Circulation 101, 1533–1538.CrossRefGoogle ScholarPubMed
Lehmann, ED, Riley, WA, Clarkson, P & Gosling, RG (1997) Non-invasive assessment of cardiovascular disease in diabetes. Lancet 350, Suppl. 1. 14–19.Google Scholar
Lewis, DS, Bertrand, HA, McMahan, CA, McGill, HC, Carey, KD & Masoro, EJ (1986) Preweaning food intake influences the adiposity of young adult baboons. Journal of Clinical Investigation 78, 899–905.Google Scholar
Lewis, DS, Mott, GE, McMahan, CA, Masoro, EJ, Carey, KD & McGill, HC (1988) Deferred effects of preweaning diet on atherosclerosis in adolescent baboons. Arteriosclerosis 8, 274–280.Google Scholar
Lloyd-Jones, DM, Larson, MG, Beiser, A & Levy, D (1999) Lifetime risk of developing coronary heart disease. Lancet 353, 89–92.Google Scholar
Lucas, A (1991) Programming by early nutrition in man. In The Childhood Environment and Adult Disease. CIBA Foundation Symposium no. 156 pp. 38–55 [Bock, GR and Whelan, J, editors] Chichester, West Sussex: Wiley.Google Scholar
McAllister, AS, Atkinson, AB, Johnston, GD & McCance, DR (1999) Relationship of endothelial function to birth weight in humans. Diabetes Care 22, 2061–2066.CrossRefGoogle ScholarPubMed
McCance, RA (1962) Food, growth and time. Lancet ii, 671–676.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Martyn, CN, Gale, CR, Jespersen, S & Sherriff, SB (1998) Impaired fetal growth and atherosclerosis of carotid and peripheral arteries. Lancet 352, 173–178.Google Scholar
Mullen, MJ, Thorne, SA & Deanfield, JE (1997) Non-invasive assessment of endothelial function. Heart 4, 297–298.Google Scholar
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. New England Journal of Medicine 327, 1350–1355.Google Scholar
Nishina, PM, Naggert, JK, Verstuyft, J & Paigen, B (1994) Atherosclerosis in genetically obese mice: the mutants obese, diabetes, fat, tubby and lethal yellow. Metabolism 43, 554–558.Google Scholar
Norman, M & Martin, H (2003) Preterm birth attenuates association between low birth weight and endothelial dysfunction. Circulation 108, 996–1001.Google Scholar
Palmer, RMJ, Ferrige, AG & Moncada, S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327, 524–526.CrossRefGoogle ScholarPubMed
Parker, C, Vita, JA & Freedam, JE (2001) Soluble adhesion molecules and unstable coronary artery disease. Atherosclerosis 156, 417–424.Google Scholar
Ren, J (2004) Leptin and hyperleptinemia – from friend to foe for cardiovascular function. Journal of Endocrinology 181, 1–10.Google Scholar
Resnick, LM, Militianu, D, Cunnings, AJ, Pipe, JG, Evelhoch, JL & Soulen, RL (1997) Direct magnetic resonance determination of aortic distensibility in essential hypertension: relation to age, abdominal visceral fat, and in situ intracellular free magnesium. Hypertension 30, 654–659.Google Scholar
Ross, R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809.CrossRefGoogle ScholarPubMed
Shaper, AG, Pocock, SJ, Phillips, AN & Walker, M (1986) Identifying men at high risk of heart attacks: strategy for use in general practice. British Medical Journal 293, 474–479.Google Scholar
Singhal, A, Cole, TJ, Fewtrell, M, Deanfield, J & Lucas, A (2004a) Is slower early growth beneficial for long-term cardiovascular health. Circulation 109, 1108–1113.Google Scholar
Singhal, A, Cole, TJ, Fewtrell, M & Lucas, A (2004b) Breastmilk feeding and lipoprotein profile in adolescents born preterm: follow-up of a prospective randomised study. Lancet 363, 1571–1578.CrossRefGoogle ScholarPubMed
Singhal, A, Cole, TJ & Lucas, A (2001a) Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials. Lancet 357, 413–419.Google Scholar
Singhal, A, Farooqi, TJ, O'Rahilly, S, Fewtrell, M, Kattenhorn, M, Lucas, A & Deanfield, J (2002a) Influence of leptin on arterial distensibility; a novel link between obesity and cardiovascular disease. Circulation 106, 1919–1924.Google Scholar
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.Google Scholar
Singhal, A, Kattenhorn, M, Cole, TJ, Deanfield, J & Lucas, A (2001b) Preterm birth, vascular function and risk factors for atherosclerosis. Lancet 358, 1159–1160.Google Scholar
Singhal, A, Lanigan, J & Lucas, A (2002b) Early origins of obesity. In Obesity in Childhood and Adolescence. Nutrition Workshop Series, 83–97 [Hen, C and Dietz, WH, editors]. Philadelphia, PA: Williams & Wilkins.Google Scholar
Singhal, A & Lucas, A (2004) Early origins of cardiovascular disease; is there a unifying hypothesis. Lancet 363, 1642–1645.Google Scholar
Singhal, A, Sadaf, I, O'Rahilly, S, Cole, TJ, Fewtrell, MS & Lucas, A (2002c) Early nutrition and leptin concentrations in later life. American Journal of Clinical Nutrition 75, 993–999.Google Scholar
Sorensen, KE, Celermajer, DS, Spiegelhalter, DJ, Georgokopoulos, D, Robinson, J, Thomas, O & Deanfield, JE (1995) Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility. British Heart Journal 74, 247–253.Google Scholar
Spalding, DA (1954) Instinct with original observations on young animals. British Journal Of Animal Behaviour 2, 2–11.Google Scholar
Stary, HC (1989) Evolution and progression of atherosclerotic lesions in coronary arteries in children and young adults. Arteriosclerosis 9, Suppl.1 I-19 – I-32.Google Scholar
Steinberg, HO, Chaker, H, Leaming, R, Johnson, A, Brechtel, G & Baron, AD (1996) Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. Journal of Clinical Investigation 97, 2601–2610.Google Scholar
Stern, MP (1996) Do non-insulin-dependent diabetes mellitus and cardiovascular disease share common antecedents. Annals of Internal Medicine 124, 110–116.CrossRefGoogle ScholarPubMed
Stettler, N, Zemel, BS, Kumanyika, S & Stallings, VA (2002) Infant weight gain and childhood overweight status in a multicenter, cohort study. Pediatrics 109, 194–199.Google Scholar
Tan, KCB, Xu, A, Chow, WS, Lam, MCW, Ai, VHG, Tam, SCF & Lam, KSL (2004) Hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. Journal of Clinical Endocrinology and Metabolism 89, 765–769.Google Scholar
Tounian, P, Aggoun, Y, Dubern, B, Varille, V, Guy-Grand, B, Sidi, D & Girardet, JP (2001) Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study. Lancet 358, 1400–1404.Google Scholar
Vanhala, M, Vanhala, P, Kumpusalo, E, Halonen, P & Takala, J (1998) Relation between obesity from childhood to adulthood and the metabolic syndrome: population based study. British Medical Journal 317, 319.CrossRefGoogle ScholarPubMed
Wallace, AM, McMahon, AD, Packard, CJ, Kelly, A, Shepherd, J, Gaw, A & Sattar, N (2001) Plasma leptin and the risk of cardiovascular disease in the west of Scotland Coronary Prevention Study (WOSCOPS). Circulation 104, 3052–3056.CrossRefGoogle ScholarPubMed
Westerbacka, J, Vehkavaara, S, Bergholm, R, Wilkinson, I, Cockcroft, J, Yki-Jarvinen, H (1999) Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity. Diabetes 48, 821–827.Google Scholar
Wheatcroft, SB, Williams, IL, Shah, AM & Kearney, MT (2003) Pathophysiological implications of insulin resistance on vascular endothelial function. Diabetes Medicine 20, 255–268.Google Scholar
Wildman, RP, Mackey, RH, Bostom, A, Thompson, T, Sutton-Tyrrell, K (2003) Measures of obesity are associated with vascular stiffness in young and older adults. Hypertension 42, 468–473.Google Scholar
Wilkinson, IB, Qasem, A, McEniery, CM, Webb, DJ, Avolio, AP & Cockcroft, JR (2002) Nitric oxide regulates local arterial distensibility in vivo. Circulation 105, 213–217.Google Scholar
Williams, IL, Wheatcroft, SB, Shah, AM & Kearney, MT (2002) Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans. International Journal of Obesity 26, 754–764.Google Scholar
Yamashita, T, Sasahara, T, Pomeroy, SE, Collier, G & Nestel, PJ (1998) Arterial compliance, blood pressure, plasma leptin, and plasma lipids in women are improved with weight reduction equally with a meat-based diet and a plant-based diet. Metabolism 47, 1308–1314.Google Scholar
Yudkin, JS (2003) Adipose tissue, insulin action and vascular disease: inflammatory signals. International Journal of Obesity 27, S25–S28.Google Scholar
Ziccardi, P, Nappo, F, Giugliano, G, Esposito, K, Marfella, R, Cioffi, M, D'Andrea, F, Molinari, AM & Giugliano, D (2002) Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 105, 804–809.Google Scholar