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 basic fibroblast growth factor (FGF) and transforming growth factor beta (TGF-beta), respectively. When co-administered with basic fibroblast growth factor (bFGF) or other exogenous mitogens, Ang II potentiates the mitogenic response. 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 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 expression. This interaction may 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/paracrine effects of Ang on VSMC growth, focusing on the balance between autocrine PDGF, FGF and TGF-beta; 2) to study the modulating role of the endothelium on Ang's action on VSMC autocrine growth factor expression and growth response using a co-culture system in vitro and Ang II administration in vivo; 3) to 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. 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 examine the role of the AT-2 receptor in mediating the altered growth of intimal cells in vitro; 5) We will study the relevance of the studies to human disease by examining the expression of Ang II receptor isoforms and ACE in atherectomy specimens. Moreover, we will obtain portions of saphenous veins at the time of bypass surgery and examine the growth of the VSMC in organ culture. 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.
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