? ? Arteries and veins must have very distinct properties responsible for each vessel's unique functional ? demands. For example, arteries, unlike veins, transmit the pressure wave and constrict to maintain ? pressure and to control blood flow. We propose that these different properties are regulated by a unique gene, or genes, found in arteries. We discovered that Regulator of G-Protein Signaling - 5 (RGS5), a member of the highly homologous R4 subfamily of RGS proteins, uniquely identifies smooth muscle cells (SMCs) from arteries relative to veins. The RGS family of proteins functions to control the duration of cellular signals mediated through G-Protein Coupled Receptors (GPCRs). RGS proteins act as GTPase Activating Proteins (GAPs) for specific GPCRs by facilitating the exchange of GDP for GTP upon G-alpha subunits of the heterotrimeric G-protein complex (Galpha/beta/gamma), thereby returning the complex to its inactive state. Our preliminary results demonstrate that arterial SMCs, relative to vein SMCs, specifically overexpress RGS5. In addition, arteries differentially express RGS5 (i.e., some arteries express RGS5 to a higher degree than others). Finally, RGS5 expression is dynamically regulated in response to vascular injury, and therefore, RGS5 may be dynamically regulated as cardiovascular disease develops. ? ? Based on these preliminary data, we hypothesize that artery-specific differences - either in physical forces acting on each vessel segment or local factors such as cell lineage or in nervation - act through specific promoter sequences to determine RGS5 protein expression level. The proposed experiments will identify and characterize the expression mechanism controlling RGS5 expression in arteries. Specifically, the experiments proposed will: (1) characterize the transcriptional regulatory mechanism controlling RGS5 mRNA expression in vitro; (2) characterize the RGS5 promoter in vivo; (3) investigate the activity of RGS5 during development an in response to vascular injury; (4) use the RGS5 promoter as a molecular model to address larger pathophysiologic questions, focusing on the likely hypothesis that functional adaptation of arteries is determined by a coordinate control mechanisms for transcription of mRNA for proteins that are key to differential arterial function. The latter goal-defining the mechanism defining arterial gene expression in response to specific local demands-is intended to provide the basis for an independent research career. (End of Abstract) ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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Special Emphasis Panel (ZHL1-CSR-M (F1))
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Scott, Jane
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University of Washington
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