How do blood vessels age? Mechanisms and clinical implications

Abstract

Ageing is one of the most important cardiovascular risk factors. Vascular ageing is determined by genetic, mechanic and hemodynamic factors. The latter is strengthened by the fact that age-associated changes in capillaries and veins, vessels which are less prone to changes in pulsatility and blood pressure, are less pronounced or even absent. Age-related morphologic changes in large resistance vessels include an intima-media thickening, increased deposition of matrix substances, thus ultimately leading to a reduced compliance. Vascular ageing is mainly characterized by an impaired endothelium-dependent vasorelaxation. The expression of endothelial nitric oxide synthase (eNOS), producing vasodilatatory nitric oxide (NO), is markedly upregulated with increasing age. However, vasorelaxation is impaired, as the production of reactive oxygen species such as superoxide (O2-), concomitantly increases. NO and O2- react to form the powerful oxidant peroxynitrite (ONOO-). Peroxynitrite is known to initiate oxidative modification of proteins, including nitration of aromatic rings, thereby rendering functionally inactive certain regulatory proteins. Deposition of nitrated proteins is mainly found within endothelial mitochondria, suggesting that mitochondrial dysfunction plays a major role in the vascular ageing process. It yet remains to be shown whether oxidative stress, which is, according to the currently accepted "oxidative stress hypothesis", a key event of vascular ageing, can be pharmacologically prevented, e.g. by naturally occurring antioxidant vitamins. However, in a mammalian model of ageing, an unexpected accumulation of vitamin E was found to accumulate within the aortic wall. This may represent a self-regulatory adaptive mechanism to prevent age-associated oxidative stress. In contrast, ascorbic acid was found to decrease with increasing age. Eventually, it remains to be seen if vitamin C or other antioxidative substances may be useful therapies. Statins and ACE inhibitors are known to have effects on mechanisms interfering with the ageing process. Given the strong age-dependency of cardiovascular disease, the developments of therapies to delay vascular ageing might have enormous medical (and economic) consequences in the future.