The relationship between aging and atherosclerosis has not been investigated to the degree warranted by the potential impact on mortality. Current theories emphasize vascular smooth muscle cell (SMC) proliferation as one important step in atherogenesis. The goal of the proposed research is to examine the effects of aging on the control of SMC proliferation. The proposed studies utilize an animal model in which we have documented that the proliferation of SMC in vitro correlates with an age related increase in vascular lesion formation in vivo. Under conditions which normally growth arrest young SMC, SMC derived from aged animals continue to proliferate at twice the rate of young SMC. Both an excess of mitogenic growth factors, such as platelet derived growth factor (PDGF) and a deficiency of inhibitory factors, such as heparin and transforming growth factor type beta (TGF-beta), may be involved in the accelerated proliferation of old SMC. The studies proposed in this grant examines the hypothesis that SMC derived from aged animals are 'disinhibited' and thereby respond rapidly and vigorously to low levels of exogenous or autocrine/paracrine mitogens like PDGF. We have documented a novel interaction between heparin, a model of cellular proteoglycans, and TGF- beta, wherein heparin prevents the inactivation of TGF-beta by alpha2- macroglobulin. By examining the cellular metabolism of TGF-beta we have preliminary data which indicate that aging may interfere with the normal production, activation, or binding of TGF-beta which would normally modulate the proliferative response of the SMC to growth stimuli. A systematically planned series of experiments investigates the effects of aging on the regulation of TGF-beta activity in SMC. Vascular SMC isolated from young adults (less than 3 mo.) or aged (more than 19 mo) rats will be cultured in vitro, and then examined for differences in their ability to produce, activate, or bind TGF-beta. The regulation of this inhibitory growth factor will be examined at the level of gene expression, protein activation, and by the ability of the cells to express its receptor. It is anticipated that these studies into the mechanism of dysregulated vascular SMC proliferation will contribute to an understanding of why aging is associated with increased incidence of severe atherosclerotic disorders.
Showing the most recent 10 out of 11 publications
