Biomedical Sciences ETDs

Publication Date

Fall 12-12-2020

Abstract

Acid-sensing ion channel 1a (ASIC1a) is a non-selective cation channel that is expressed in vascular smooth muscle cells. However, little is known about the contribution of ASIC1a to vascular reactivity and cardiovascular homeostasis. We have previously shown that ASIC1a contributes to pulmonary vascular smooth muscle cell (VSMC) Ca2+ entry and vasoconstriction as well as chronic hypoxia-induced pulmonary hypertension. However, a role of ASIC1a in the systemic circulation is unclear. Previous reports have shown that ASIC1a is expressed in femoral and cerebral arteries, however, these studies suggest that ASIC1a contributes to vascular reactivity through neuronal regulation rather than vascular. Therefore, in this current study, we investigated the role of vascular ASIC1a in the systemic circulation. We hypothesized that the expression of ASIC1a in mesenteric vascular smooth muscle and endothelium leads to the regulation of mesenteric vascular reactivity independent of neuronal control.

To test this hypothesis, we used various ex vivo techniques to assess the role of ASIC1a in isolated pressurized arteries and mesenteric endothelial tubes. We found that unlike pulmonary arteries, ASIC1a does not contribute to mesenteric VSMC Ca2+ entry or mesenteric vasoconstriction in response to agonists or store-operated Ca2+ entry. Interestingly, further investigation found that ASIC1a contributes to mesenteric endothelial cell Ca2+ entry and mesenteric vasodilation in response to acetylcholine. Additionally, studies revealed that ASIC1a contributes to endothelial-derived hyperpolarization factor (EDHF)-mediated vasodilation, similar to small and intermediate conductance Ca2+-activated K+ channels (SK and IK).

In conclusion, we show that ASIC1a plays a unique role in regulating reactivity of different vascular beds. ASIC1a contributes to VSMC Ca2+ entry and vasoconstriction in the pulmonary circulation and endothelial cell Ca2+ entry and vasodilation in the mesenteric circulation. As the endothelium is a critical regulator in cardiovascular homeostasis and endothelial dysfunction, ASIC1a could be a potential therapeutic target for the treatment of cardiovascular diseases.

Keywords

acid sensing ion channel 1a, ASIC1, store operated calcium entry, endothelium derived hyperpolarization factor

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Nikki L. Jernigan

Second Committee Member

Thomas C. Resta

Third Committee Member

Nancy L. Kanagy

Fourth Committee Member

Jay S. Naik

Fifth Committee Member

Jennifer M. Gillette

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