Biomedical Sciences ETDs

Publication Date

12-1-2011

Abstract

Vasoconstrictor responsiveness of the systemic circulation is attenuated following prolonged exposure to hypoxia. Previous work from our laboratory has demonstrated vasoconstrictor reactivity is diminished due to hyperpolarization of the vascular wall in systemic arterioles. The hyperpolarization of the vascular wall was found to be dependent upon the endothelium, heme oxygenase (HO), and calcium-activated large conductance potassium channel (BKCa) as removal of the endothelium or blockade of HO or BKCa restored vasoreactivity. Interestingly, recent evidence for HO and BKCa association has emerged in carotid body glomus cells where HO and BKCa form oxygen sensing complexes. In these novel oxygen sensing complexes, HO-derived CO activates BKCa channels in localized domains that regulate carotid body membrane potential. The presence and function of HO and BKCa association has not been previously acessed in the systemic endothelium. The following studies investigated a novel HO-BKCa functional unit in systemic vascular endothelial cells. In whole cell patch clamp experiments it was demonstrated that HO-dependent activation of BKCa significantly increased transmembrane currents in ECs following CH. Additionally, HO-dependent BKCa activity was unearthed following disruption of caveolin-1 function or potentially inhibited following incubation with the caveolin-1 scaffolding domain, demonstrating the inhibitory role of caveolin-1 on HO-BKCa complexes. Membrane potential recordings and isolated arteriole experiments further demonstrated EC BKCa regulates EC Em and vasoconstrictor reactivity following CH through a loss in caveolin-1 inhibition. This study is the first to characterize HO-dependent BKCa activation regulation by caveolin-1 and demonstrate a functional role for endothelial BKCa in vascular tone.

Keywords

Caveolin-1, Calcium-activated large conductance potassium channel

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Walker, Benjimen

First Committee Member (Chair)

Resta, Thomas

Second Committee Member

Gonzales-Bosc, Laura

Third Committee Member

Kanagy, Nancy

Fourth Committee Member

Valenzuela, Fernando

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