Physiological regulation of vascular function by mutant caveolin-1

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DESCRIPTION (provided by applicant): Inhibition of eNOS function by endogenous caveolin-1 (Cav-1) has been well characterized in vitro and in vivo. We have further dissected the interaction between eNOS and Cav-1, and have dissociated the inhibitory binding of Cav-1 to eNOS using mutagenesis of the caveolin scaffolding domain (CSD). AP-Cav 3PM, a cell permeable peptide harboring a mutant form of the Cav-1 CSD, activates eNOS in vitro and ex vivo. Importantly we have now developed inducible, endothelial cell specific Cav-1 transgenic mice that have a mutant form of Cav-1 (F92A Cav-1) that promotes NO release through the dissociation of Cav-1 and eNOS. With this in mind, understanding the interactions between eNOS and Cav-1 will permit molecular dissection of the roles of Cav-1 as a negative regulator of eNOS and the role this plays angiogenesis. We hypothesize that F92A Cav-1 mutant mice will exhibit structurally normal caveolae and Cav-1 distribution, in addition to increased NO production, reduced blood pressure, lower vascular reactivity, and increased angiogenic potential. Excitingly, this proposal presents the first in vivo platform for the study of Cav-1 physiological role as the major structural component of caveolae versus its role as a signaling platform. To examine the regulation of this important interaction in more detail, we will determine:1 The effects of the F92A Cav-1 mutation on the cardiovascular phenotype in vivo; 2. The effects of the F92A Cav-1 mutation on physiologic responses of the vasculature ex vivo and 3. How the F92A Cav-1 mutation affects angiogenesis in vivo. PUBLIC HEALTH RELEVANCE: Project Narrative This research is relevant to public health since endothelial dysfunction is a common manifestation of most cardiovascular diseases. Our research will design new approaches to improve blood flow and reduce atherogenesis. Research supported by this grant may help identify pathways and molecular targets that reduce heart disease and improve the quality of life of people suffering with cardiovascular disease.