Angiotensin (Ang) is a bifunctional growth factor of vascular smooth muscle cells (VSMC) in vitro. It stimulates simultaneously proliferative and antiproliferative pathways that appear to be mediated by the activation of autocrine platelet derived growth factor (PDGF AA) and transforming growth factor beta (TGF-beta), respectively. When co-administered with basic fibroblast growth factor (bFGF) or other exogenous mitogens, Ang II potentiates markedly the mitogenic responses. In vivo, however, Ang II has a weak stimulatory effect on VSMC PDGF expression and growth in blood vessels with intact endothelium. We hypothesize that the endothelium plays an important role in modulating VSMC growth as well as the expressions of autocrine growth factors and the vascular renin angiotensin system. With endothelial injury and basement membrane disruption, Ang acts synergistically with bFGF and other mitogens (e.g. PDGF AB of platelet origin) that are activated under this condition to promote VSMC proliferation and gene expressions. This interaction of growth factors may mediate or accelerate the process of myointimal hyperplasia. Indeed, ACE inhibitors have been shown to attenuate the vascular myoproliferative lesion in vivo in response to balloon injury. This proposal will examine this important endothelial cell-renin angiotensin (RAS) interaction in normal and injured blood vessels.
The specific aims are: 1) to study the cellular mechanisms of the autocrine PDGF and TGF-beta; 2) to study the modulating role of the endothelium on Ang's action on VSMC autocrine growth factor expressions and growth response using a co-culture system; 3) we will examine the in vivo relevance of the endothelial cell-RAS interaction by studying vascular proliferation and autocrine growth factor response to endothelial injury in vivo and the effect of ACE inhibitors and selective Ang antagonists; 4) we will identify the origin of vascular Ang at the site of injury. We will examine if the local Ang is the result of enhanced uptake from the plasma or increased local expression of the RAS. 5) We will investigate the possible causal relationship between the vascular renin angiotensin system and the autocrine growth factor induction using in vivo site-specific gene (antisense) transfer techniques. The above studies are logical extensions of our original studies on endothelial cell-RAS interactions and propose to take our research to a novel and important arena, i.e. the pathophysiological role of altered vascular RAS in vascular disease such as myointimal hyperplasia.
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