Lumenal narrowing due to excessive growth of arterial smooth muscle cells (SMC) plays a critical role in the pathologic basis of artery wall diseases including hypertension and atherosclerosis. The discovery that arterial SMC can produce their own growth factors raises new questions about the signals that control growth factor synthesis in intact arteries and the ways that these signals are coupled to normal circulatory demands and disease. We recently showed that alpha1-adrenergic receptor (alpha1-AR) stimulation increased platelet-derived growth factor A-chain (PDGF-A) expression in rat aorta and found that the PDGF alpha-receptor is also expressed in this vessel. In the work proposed here, we will explore predictions of the hypothesis that alpha1-AR regulation of PDGF-A expression provides a mechanism linking chronic sympathetic nerve activity and elevated plasma catecholamines to long-term trophic changes in arterial SMC mass and wall thickness. Using RNA blot analysis, RNase protection assays, immunohistochemistry, and in situ hybridization techniques, we will measure and localize PDGF-A and PDGF alpha-receptor in selected adult rat arteries after alpha1-AR stimulation. Employing the methods thus established, we will then examine three important predictions of our hypothesis: (1) We will determine if direct electrical stimulation of sympathetic nerves supplying the artery wall can itself increase PDGF-A expression. (2) We will examine selected arteries from young rats at ages when nerve-muscle trophic effects are most pronounced and ask: Do these vessels also show alpha1-AR-stimulation of PDGF-A and/or PDGF alpha- receptor expression? Where are the responding cells localized within the vessel wall? Are other growth factors known to modify PDGF-A action also regulated by alpha1-ARs? (3) We will use neutralizing antibodies to PDGF- AA in attempts to show a functional role for this growth factor in SMC growth responses to alpha1-AR stimulation in vitro. Our previous finding that alpha1-AR stimulation increases aortic PDGF-A expression raises important new questions about the role of the alpha1-AR in SMC growth control and emphasizes a need to know more about the nature of endogenous mechanisms that couple paracrine growth factor production to circulatory demands within the artery wall.
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