A major disease of the elderly, atherosclerosis represents a process involving proliferative as well as degenerative changes in arteries. Our hypothesis is that ageing may result in altered growth regulation of artrial smooth muscle cells, leading to proliferative changes normally restricted to early development or injury repair. We propose to study the impaired regulation of vascular smooth muscle cell proliferation in aged individuals using inbred rats to permit comparison of old and young individuals, as well as transplantation of vessel segments to compare environmental with age-related influences. Preliminary studies have indicated that proliferation of vascular smooth muscle cells is greater in old than in young rats in three separate experimental settings: following arterial injury, following transplantation of arterial segments from old animals to young, and following explanation of arterial smooth muscle cells in tissue culture. This suggest that factors intrinsic to the old smooth muscle cells, possibly autocrine expression of growth regulatory factors, rather than the environment, determine the proliferative responses which lead to atherosclerotic lesions. We will examine the possible expression of growth factors such as PDGF by SMC from old animals compared to young, activation and amplification of cellular oncogenes involved in growth control, such as c-sis and c-myc, response to exogenous growth stimulatory factors and inhibitory factors such as prostaglandins and heparin, and the effect of extracellular matrix produced by SMC of different ages on SMC proliferation and function. The role of hyperlipidemia in augmenting SMC proliferation will be explored using an inbred hypercholesterolemic strain of rat. The experimental approach will combine tissue culture and whole animal studies. The overall goal of these studies is to achieve a clearer understanding of the molecular control of vascular proliferation in relation to the ageing process.
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