Ross' hypothesis suggests that atherosclerotic lesions develop in response to endothelial damage and subsequent platelet adherence and release of growth factors. This hypothesis has recently been expanded to cover the possiblility that the lesions occur as a result of an endogenous process i.e., local hormonal imbalance, in the arterial wall as it has become clear that mitogens can be produced by cells in the arterial wall. Here we propose to study the effects of growth factors and growth factor interactions on the proliferation of and proteoglycan metabolism in cultured human vascular bed cells in low-serum and serum-free media. Purified growth factors to be used include epidermal growth factor (EGF), platelet-derived growth factor (PDGF), heparin- binding growth factors (ECGF-1), human platelet-derived transforming growth factor-beta (beta-TGF) and low density lipoprotein (LDL). These factors are either stored in or secreted by cells involved in vascular bed cell interactions, or are believed to be implicated in atherogenesis. Preliminary results indicate that human platelet-derived beta-TGF specificially stimulated synthesis of at least two types of proteoglycans in nonproliferating human adult arterial smooth muscle cells in culture. Stimulation of smooth muscle cell proteoglycan synthesis by smooth muscle cell growth promoters (EGF, PDGF and ECGF- 1) was less than 20% of that elicited by beta-TGF. Beta-TGF neither significantly stimulated proliferation of quiescent smooth muscle cells nor inhibited proliferating cells. The extent of beta- TGF stimulation of smooth muscle cell proteoglycan synthesis was similar in both non-proliferating and growth-stimulated cells. Beta-TGF, which is a reversible inhibitor of endothelial cell proliferation, had no comparable effect on endothelial cell proteoglycan synthesis. We will further investigate the effect of growth factor interactions on smooth muscle and endothelial cell growth and proteoglycan metabolism to further dissect the relation between these two cellular functions, and structurally characterize proteoglycan molecules whose synthesis is specifically stimulated by beta-TGF.
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