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.
Cardiovascular disease is the leading cause of death in the United States. Post-menopause and hypertension are major risk factors. Age-matched men are generally at greater risk than premenopausal women for cardiovascular disease;however, after menopause women lose their cardioprotection. Female hormone, estrogen, may regulate endothelial potassium channels to modulate vascular reactivity and blood pressure.
|Yap, Fui C; Weber, David S; Taylor, Mark S et al. (2016) Endothelial SK3 channel-associated Ca2+ microdomains modulate blood pressure. Am J Physiol Heart Circ Physiol 310:H1151-63|
|Lin, Mike T; Jian, Ming-Yuan; Taylor, Mark S et al. (2015) Functional coupling of TRPV4, IK, and SK channels contributes to Ca(2+)-dependent endothelial injury in rodent lung. Pulm Circ 5:279-90|
|Yap, Fui C; Taylor, Mark S; Lin, Mike T (2014) Ovariectomy-induced reductions in endothelial SK3 channel activity and endothelium-dependent vasorelaxation in murine mesenteric arteries. PLoS One 9:e104686|
|Lin, Mike T; Adelman, John P; Maylie, James (2012) Modulation of endothelial SK3 channel activity by Caýý+dependent caveolar trafficking. Am J Physiol Cell Physiol 303:C318-27|