Vascular Smooth Muscle and Endothelial Functions in Aging

Abstract

Aging is one of the main risk factors for the development of atherosclerosis and, therefore, for coronary artery disease. Age-associated remodeling of the vascular wall includes luminal enlargement, intimal and medial thickening, and increased vascular stiffness. As aging occurs, smooth muscle cells (SMCs) progressively migrate from the tunica media and accumulate into the tunica intima. Aging also associates with changes of SMC proliferative and apoptotic behavior and response to growth factors, such as transforming growth factor-beta1. Aging induces a reduction in the density of the alpha-subunit of Ca(2+)-activated K(+) channels in coronary smooth muscle and increases the response to endothelial constrictor factors and K(+). Accordingly, we have recently shown that the vasodilatory effect of male sex hormone testosterone, which is mediated through large conductance Ca(2+)-activated K(+) channel opening action, decreases with age. Apart from age-associated remodeling of the vascular wall, endothelial function declines with age. This is most obvious from the attenuation of endothelium-dependent dilator responses, which is a consequence of the alteration in the expression and/or activity of the endothelial nitric oxide (NO) synthase, upregulation of the inducible NO synthase, and increased formation of reactive oxygen species. In fact, in the course of aging, there is an alteration in the equilibrium between relaxing and contracting factors released by the endothelium. Hence, there is a progressive reduction in the participation of NO and endothelium-derived hyperpolarizing factor (EDHF) associated with increased participation of oxygen-derived free radicals and cyclooxygenase-derived prostanoids. Also, the endothelin-1 and angiotensin II pathways may play a role in age-related endothelial dysfunction. Aging is also associated with a reduction in the regenerative capacity of the endothelium and endothelial senescence, which is characterized by an increased rate of endothelial cell apoptosis. Thus, aging elicits several changes in the vascular endothelium gradually altering its phenotype from an anti- to a proatherosclerotic one. In conclusion, it becomes increasingly evident that the blood vessel structural and functional disturbances, which characterize vascular aging, make a major contribution to aging-related target organ damage. The use of drugs, including antioxidant therapy, lipid-lowering drugs, and estrogens, seems to be promising.