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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL102056-04
Application #
8532961
Study Section
Special Emphasis Panel (NSS)
Program Officer
Galis, Zorina S
Project Start
2010-09-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$199,347
Indirect Cost
$54,142
Name
University of South Alabama
Department
Physiology
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688