Endothelial SK3 Channel Modulation of EDHF is Estrogen Regulated

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The vascular endothelium infiuences vascular tone in part through the Ca^*-dependent endothelium-derived hyperpolarizing factor (EDHF). In response to cholinergic stimulation (e.g. acetylcholine, ACh), a transient elevation of [Ca^*]j activates apamin-sensitive, voltage-independent Ca^*-activated K"^ channels, SKS channels, which hyperpolarize the endothelial membrane potential, resulting in EDHF-mediated vasodilation The central importance of endothelial SKS channels is dramatically illustrated by the hypertension seen in mice with reduced SKS expression levels. Endothelial SKS channels are localized within caveolae dynamically trafficked surface invaginations and cytoplasmic vesicles that juxtapose receptors, ion channels, transporters, and signaling molecules that mediate the transport of humoral molecules across the endothelia barrier. Indeed, SKS channels co-immunoprecipitate (co-IP) with the structural protein of caveolae, caveolin- 1, and disruption of caveolar structure inhibits EDHF-mediated vasorelaxation. Further, the regulation of vascular tone and SKS gene transcription are sensitive to estrogen (E2), giving rise to increased risk of hypertension following menopause or surgical ovariectomy. Supported by my preliminary results showing for the first time that caveolar trafficking modulates SKS channel activity, the goal of this proposal is to study how trafficking of endothelial SKS channels regulates vasodilatation via EDHF and how estrogen modulates these processes. I will use an integrated repertoire of electrophysiology, vascular reactivity, biochemistry molecular biology, and electron microscopy.