Endothelium is a key regulator of blood pressure. Loss of endothelium-dependent vasodilation is an important contributor to obesity-induced hypertension. Under normal conditions, increase in endothelial cell Ca2+ promotes vasodilation. However, endothelial Ca2+ signaling mechanisms in resistance arteries that determine blood pressure have not been explored in obesity. Endothelial cell TRPV4 channels (TRPV4EC), a major Ca2+ influx pathway in the endothelium, lower resting blood pressure. Moreover, the activity of TRPV4EC channels is impaired in obesity, which contributes to obesity-induced hypertension. We recently identified reactive nitrogen species peroxynitrite as the signaling molecule that lowers TRPV4EC channel activity in obesity. However, the signaling mechanisms that contribute to increased peroxynitrite levels in obesity remain unknown. Peroxynitrite is formed by the reaction between nitric oxide and superoxide radicals. Here, I hypothesize that elevated levels of endothelial iNOS and NOX1 enzymes contribute to peroxynitrite-dependent impairment of TRPV4EC channels. I also propose studies that will provide the clinical relevance of PN-dependent TRPV4EC channel impairment in obesity. In Aim 1, I will determine the role of elevated endothelial NOX1 in peroxynitrite-dependent impairment of TRPV4EC channel activity in obese individuals and mice. In Aim 2, I will determine the role of elevated endothelial iNOS in peroxynitrite-dependent inhibition of TRPV4EC channel activity in obese individuals and mice. Studies in this application will provide clinically relevant mechanisms and novel therapeutic targets for obesity-induced endothelial dysfunction and hypertension.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 06/30/2022|