Smooth muscle cell (SMC) proliferation and intimal hyperplasia are a general response to vascular injury and grafting, and when excessive, lead to lumenal narrowing, decreased blood flow, and thrombosis. Although many of the factors regulating medial SMC proliferation and migration in injured artery have been defined, it is not at all evident what factors regulate intimal mass. We have shown that endothelial denudation or, in vessels covered with endothelium, a change in blood flow from high to normal generates a signal for intimal thickening. Both manipulations of the vasculature cause a decrease in the expression of endothelial nitric oxide synthase (ecNOS) and an increase in one of the isoforms of platelet-derived growth factor (PDGF-A chain). We propose to test the hypothesis that intimal SMC proliferation and matrix accumulation are controlled by the SMC growth inhibitor nitric oxide (NO) expressed by the endothelium and that the induction of SMC growth is due as much to a decrease in NO as an increase in growth promoting factors (possibly PDGF). The hypothesis that SMCs in normal and artificial blood vessels are under negative growth control provides a general explanation for intimal thickening in the absence or presence of endothelium. We propose a combined in vitro and in vivo approach using cultured baboon endothelium and SMCs transduced with a replication-defective retrovirus encoding human ecNOS and baboon models of intimal hyperplasia.
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