Peripheral vascular resistance increases with age resulting in the development of systolic hypertension. This phenomenon is associated with arterial stiffening which is modulated by vascular tonus as well as by structural changes in the arterial wall. The goal of these studies is to characterize the structural changes within the rat aortic wall during aging and to elucidate the mechanism(s) responsible for age-associated remodeling of the vasculature. Tail cuff systolic blood pressure in Fisher 344XNB rats increased by 33.8% (p<.001) between 6 and 30 months of age without a change in diastolic pressure. Morphometric analysis of the aortic wall revealed a significant age-associated increase in vessel diameter (25.6%) and wall thickness (38.4%) and a decrease in medial wall cellularity (18.4%). In old animals, frequent breaks in the elastic laminae were observed together with a 5-fold increase the subendothelial intimal space and the occasional appearance of smooth muscle cells. Immunohistochemical studies revealed increased expression of ICAM-1 and TGF-b in the thickened intima of old rat aortae. Consistent with this, the levels of fibronectin and TGF-b in aortic extracts from old rats were significantly elevated. Compared to young rats, zymograms of tissue extracts from old rats showed increased activity of both the activated and inactivated forms of matrix metalloprotease-2 (MMP-2). The increased expression of adhesive molecules in old animals may attract monocytes to the vessel wall, providing a source of mitogenic factors and cytokines for extracellular matrix (ECM) remodeling. Accompanying the increase in TGF-b and activated MMP-2 in senescent aortae, smooth muscle cell migratory activity and ECM protein secretion are enhanced. These structural modifications, leading to an increased wall thickness and decreased cellularity, are likely to be important factors contributing to the increase in arterial stiffeness and peripheral resistance associated with vascular aging.
