Friday, July 26, 2024
7/26/2024
DESCRIPTION (provided by applicant): Small (resistance-size) cerebral arteries and arterioles control regional brain blood flow, thereby providing neurons and other brain cells with necessary oxygen and nutrients. An essential regulator of artery contractility is smooth muscle cell membrane potential, which is controlled by ion channels. Hypertension is associated with increased risk for cerebral diseases, including stroke and dementia. Cerebral arteries from hypertensive subjects are depolarized, leading to elevated contractility, but mechanisms involved in this pathological alteration are unclear. Previous studies have focused on identifying mechanisms that regulate the activity of ion channels located in the plasma membrane of arterial smooth muscle cells. In contrast, mechanisms that control the number of functional ion channels and their auxiliary subunits in the plasma membrane of smooth muscle cells are unclear. Large-conductance calcium (Ca2+)-activated potassium (BKCa) channels are a major physiological modulator of arterial smooth muscle cell membrane potential and contractility. Arterial smooth muscle cells express two BKCa channel subunits: a pore-forming ¿(BK¿) and an auxiliary ¿1 that is essential for channel physiological functions. This application stems from novel preliminary data indicating that physiological stimuli control BK¿ and ¿1 surface expression to modulate channel subunit composition, channel activity and arterial contractility. We also provide evidence that hypertension is associated with pathological alterations in mechanisms that regulate BKCa channel subunit surface expression, thereby promoting vasoconstriction. Three specific aims will be investigated to test the central hypothesis that vasoregulatory stimuli modulate surface expression of BKCa channel subunits to control cerebral artery contractility, and that pathological modification of these processes leads to vasoconstriction associated with cerebrovascular disease. Aim 1 will examine the hypothesis that vasodilators and vasoconstrictors regulate ¿1 subunit surface expression to control BKCa channel activity in smooth muscle cells and arterial contractility. Aim 2 will investigate the hypothesis that vasoconstrictors and vasodilators modulate BK¿ surface expression and degradation to regulate smooth muscle cell BKCa channel activity and arterial contractility. Aim 3 will explore the hypothesis that hypertension is associated with dysfunctional control of BK¿ and ¿1 subunit surface expression that stimulates vasoconstriction. Methods used to test these hypotheses will include arterial biotinylation, FRET, RNAi, co-IP, immunofluorescence, patch-clamp electrophysiology, membrane potential recording, intracellular Ca2+ imaging and arterial myography. This proposal will provide significant novel information concerning cerebral artery contractility regulation by physiological and pathological mechanisms that control BKCa channel surface expression.
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