Aging and vascular endothelial function in humans

Abstract

Advancing age is the major risk factor for the development of CVD (cardiovascular diseases). This is attributable, in part, to the development of vascular endothelial dysfunction, as indicated by reduced peripheral artery EDD (endothelium-dependent dilation) in response to chemical [typically ACh (acetylcholine)] or mechanical (intravascular shear) stimuli. Reduced bioavailability of the endothelium-synthesized dilating molecule NO (nitric oxide) as a result of oxidative stress is the key mechanism mediating reduced EDD with aging. Vascular oxidative stress increases with age as a consequence of greater production of reactive oxygen species (e.g. superoxide) without a compensatory increase in antioxidant defences. Sources of increased superoxide production include up-regulation of the oxidant enzyme NADPH oxidase, uncoupling of the normally NO-producing enzyme, eNOS (endothelial NO synthase) (due to reduced availability of the cofactor tetrahydrobiopterin) and increased mitochondrial synthesis during oxidative phosphorylation. Increased bioactivity of the potent endothelial-derived constricting factor ET-1 (endothelin-1), reduced endothelial production of/responsiveness to dilatory prostaglandins, the development of vascular inflammation, formation of AGEs (advanced glycation end-products), an increased rate of endothelial apoptosis and reduced expression of oestrogen receptor α (in postmenopausal females) also probably contribute to impaired EDD with aging. Several lifestyle and biological factors modulate vascular endothelial function with aging, including regular aerobic exercise, dietary factors (e.g. processed compared with non-processed foods), body weight/fatness, vitamin D status, menopause/oestrogen deficiency and a number of conventional and non-conventional risk factors for CVD. Given the number of older adults now and in the future, more information is needed on effective strategies for the prevention and treatment of vascular endothelial aging.

Figure 1. Vascular endothelial dysfunction and risk of CVD with aging

Vascular endothelial dysfunction is characterized by a shift from a vasodilatory, anti-coagulative, anti-proliferative and anti-inflammatory state to a vasoconstrictor, pro-coagulative, pro-proliferative and pro-inflammatory state, leading to an increased risk of cardiovascular disease with aging.

Figure 2. Models to assess EDD in humans

Brachial artery FMD and FBF models for assessing EDD.

Figure 3. Endothelial eNOS protein expression and activation with aging in men

In vascular endothelial cells collected from the brachial artery of healthy human subjects, eNOS protein expression tends to be greater in older compared with young subjects, whereas eNOS phosphorylated at Ser¹¹⁷⁷ is significantly increased, suggesting a greater state of activation of the enzyme with aging. *P < 0.05 compared with young subjects; values are ratios to HUVEC control; representative images are shown below the histograms. Reproduced from [65], with permission. © (2009) The American Physiological Society.

Figure 4. BH₄ and impaired EDD with aging in men

Administration of BH₄ improves endothelium-dependent dilation in middle-aged/older adults, as measured by FBF in response to ACh (upper panel) and brachial artery FMD (lower panel). *P < 0.05 compared with young adults. The upper panel was reprinted from Atherosclerosis, volume 186, Higashi, Y., Sasaki, S., Nakagawa, K., Kimura, M., Noma, K., Hara, K., Jitsuiki, D., Goto, C., Oshima, T., Chayama, K. and Yoshizumi, M., Tetrahydrobiopterin improves aging-related impairment of endothelium-dependent vasodilation through increase in nitric oxide production, pp. 390–395, copyright (2006), with permission from Elsevier (http://www.sciencedirect.com/science/journal/00219150). The lower panel was re-drawn from data in [60].

Figure 5. Endothelial nitrotyrosine and EDD with aging in men

Brachial artery endothelial cell staining for nitrotyrosine is greater in older compared with young healthy subjects (upper panel) and is inversely related to brachial artery FMD in the overall group (lower panel). *P = 0.01 compared with young adults. Values are ratios to HUVEC control and representative images are shown below the histogram. Reproduced with permission from Donato, A.J., Eskurza, I., Silver, A.E., Levy, A.S., Pierce, G.L., Gates, P.E. and Seals, D.R., Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-κB, Circ. Res. 100 (11), pp. 1659–1666. © (2007) Wolters Kluwer Health.

Figure 6. Oxidative-stress-related impairment of EDD with aging in humans

Acute administration of ascorbic acid (vitamin C) improves EDD in older adults, as measured by FBF to ACh (left-hand and middle panels) and brachial artery FMD (right-hand panel). *P < 0.05 compared with young adults. The left-hand and middle panels were reproduced with permission from Taddei, S., Galetta, F., Virdis, A., Ghiadoni, L., Salvetti, G., Franzoni, F., Giusti, C. and Salvetti, A., Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes, Circulation 101 (25), pp. 2896–2901. © (2000) Wolters Kluwer Health. The right-hand panel was re-drawn from data in [58].

Figure 7. Endothelial NADPH oxidase and ET-1 with aging in humans

Brachial artery endothelial cell protein expression of (A) NADPH oxidase and (B) ET-1 are greater in older and young healthy adults. *P < 0.05 compared with young adults. Values are ratios to HUVEC control, and representative images are shown below the histograms. The results in (A) are from A.J. Donato, G.L. Pierce and D.R. Seals, unpublished work. Panel (B) was reproduced from [65], with permission. © (2009) The American Physiological Society.

Figure 8. Endothelial pro-inflammatory proteins and aging in humans

In vascular endothelial cells obtained from an antecubital vein, expression of NF-κB, MCP-1, IL-6 and TNF-α are greater in older compared with young adults. *P < 0.05 compared with young adults. Values are ratios to HUVEC control, and representative images are shown below the histograms. Reproduced from Donato, A.J., Black, A.D., Jablonski, K.L., Gano, L.B. and Seals, D.R., Aging Cell, with permission. © (2008) Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland (http://onlinelibrary.wiley.com/journal/10.1111/%28ISSN%291474-9726).

Figure 9. ERα and EDD with aging in women

In vascular endothelial cells obtained from an antecubital vein, ERα expression is lower in oestrogen-deficient postmenopausal women compared with premenopausal women in the late follicular (LF; high oestrogen), but not early follicular (EF; low oestrogen) phase (upper panel) and is related to brachial artery FMD in the overall group (lower panel). *P < 0.001 compared with LF. Values are ratios to HUVEC controls, and representative images are shown below the histograms. Reproduced with permission from Gavin, K.M., Seals, D.R., Silver, A.E. and Moreau, K.L., J. Clin. Endocrinol. Metab., Vascular endothelial estrogen receptor α is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women, volume 94 (9), September 2009, pp. 3513–3520. Copyright 2009, The Endocrine Society.

Figure 10. Regular aerobic exercise and EDD with aging in men

FBF responses to ACh in sedentary (top panel) and endurance-exercise-trained (middle panel) healthy young and middle-aged/older men and before and after an aerobic exercise intervention in older men (bottom panel). *P < 0.05. Reproduced from DeSouza, C.A., Shapiro, L.F., Clevenger, C.M., Dinenno, F.A., Monahan, K.D., Tanaka, H. and Seals, D.R., Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men, Circulation, volume 102 (12), pp. 1351–1357. © (2000) Wolters Kluwer Health.

Figure 11. Dietary sodium intake and EDD in middle-aged and older adults

Brachial artery FMD is greater in middle-aged/older adults consuming low (73 ± 6 mmol/day) compared with normal (144 ± 6 mmol/day) sodium in their diet (upper panel) and is inversely related to dietary sodium intake among individuals (lower panel). *P < 0.05. Reproduced with permission from Jablonski, K.L., Gates, P.E., Pierce, G.L. and Seals, D.R., Low dietary sodium intake is associated with enhanced vascular endothelial function in middle-aged and older adults with elevated systolic blood pressure, Ther. Adv. Cardiovasc. Dis., volume 3, pp. 347–356. Copyright © (2009) by SAGE Publications (http://online.sagepub.com).

Figure 12. Weight loss and NO-mediated EDD in young, middle-aged and older adults

Energy-intake-restriction-induced body weight loss alone improves both brachial artery FMD (upper panel) and NO-mediated FBF_ACh (lower panel) in young and middle-aged/older overweight and obese adults. *P < 0.05 compared with baseline; †P < 0.05 for the dose–time interaction. Reproduced with permission from Pierce, G.L., Beske, S.D., Lawson, B.R., Southall, K.L., Benay, F.J., Donato, A.J. and Seals, D.R., Weight loss alone improves conduit and resistance artery endothelial function in young and older overweight/obese adults, Hypertension, volume 52 (1), pp. 1–8. © (2008) Wolters Kluwer Health.

Figure 13. Vitamin D status, receptor expression and EDD in middle-aged and older adults

Brachial artery FMD is lower in vitamin D-deficient/-insufficient adults compared with sufficient middle-aged/older adults (top panel) and is positively related to serum 25-hydroxyvitamin D [25[OH)D] among individuals (middle panel). Vitamin D-deficient/-insufficient adults have lower endothelial cell vitamin D receptor expression (bottom panel). Values are means ± S.E.M. *P < 0.01 compared with deficient adults; †P < 0.05 compared with insufficient adults; ‡P < 0.05 compared with deficient adults. Values are ratios to HUVEC control, and representative images are shown below the histogram. Reproduced with permission from Jablonski, K.L., Chonchol, M., Pierce, G.L. Walker, A.E. and Seals, D.R., 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults, Hypertension, volume 57 (1), pp. 63–69. © (2011) Wolters Kluwer Health.

Figure 14. Blood pressure and EDD with aging in humans

Older patients with essential hypertension (HTN) have lower brachial artery FMD (upper panel) and peak FBF to ACh (lower panel) compared with older adults with normal blood pressure. *P < 0.05 compared with older normal adults; †P < 0.01 compared with young adults. BP, arterial blood pressure. These results are from K.L. Jablonski, G.L. Pierce, A.J. Donato, A.E. Walker and D.R. Seals, unpublished work.

Figure 15. LDL-cholesterol and EDD with aging in men

In contrast with young controls, middle-aged/older adults with borderline high LDL-cholesterol have impaired brachial artery FMD compared with peers with optimal/near-optimal LDL-cholesterol. *P < 0.05 compared with young adults with optimal/near-optimal LDL-cholesterol; †P < 0.05 compared with older with optimal/near-optimal LDL-cholesterol. Reprinted by permission from Macmillan Publishers Ltd: American Journal of Hypertension (Walker, A.E., Eskurza, I., Pierce, G.L., Gates, P.E. and Seals, D.R. (2009) Modulation of vascular endothelial function by low-density lipoprotein cholesterol with aging: influence of habitual exercise, volume 22, pp. 250–256), copyright (2009) (http://www.nature.com/ajh/index.html).

Figure 16. White blood cell count and EDD with aging in humans

Older adults with a higher white blood cell (WBC) count have impaired FBF_ACh compared with older adults with lower WBC (*P < 0.05) and young adults. Reproduced with permission from Walker, A.E., Seibert, S.M., Donato, A.J., Pierce, G.L. and Seals, D.R., Vascular endothelial function is related to white blood cell count and myeloperoxidase among healthy middle-aged and older adults, Hypertension, volume 55 (2), pp. 363–369. © (2010) Wolters Kluwer Health.