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.