Thursday, May 2, 2024
5/2/2024
ABSTRACT Endothelial calcium signaling mechanisms regulate vascular function and blood pressure. In obesity, impaired endothelial calcium signaling results in the loss of endothelium-mediated dilation and elevation of blood pressure. The goal of this application is to identify targetable abnormalities in endothelial calcium signaling mechanisms in obesity. Our recent studies show that TRPV4 channels, a crucial calcium entry pathway in endothelial cells, lower blood pressure under normal conditions. Moreover, increased formation of peroxynitrite, a reactive nitrogen species, reduces the activity of endothelial TRPV4 channels and elevates blood pressure in obesity. Tumor necrosis factor (TNF), an inflammatory cytokine, is a well-known promoter of cellular peroxynitrite formation. Our preliminary data show that TNF is selectively upregulated in the vascular smooth muscle cells in obesity. Therefore, we will determine the role of smooth muscle cell TNF and endothelial cell TNF receptor I (TNFRI) in increasing endothelial peroxynitrite levels and impairing endothelial calcium signaling in diet-induced obesity. We will use newly developed cell-specific knockout mice for TNF and TNFRI in combination with peroxynitrite and TRPV4 channel measurements in small arteries. Also, mineralocorticoid receptor (MR) activation has been linked with increased TNF levels and endothelial dysfunction. Therefore, we will delineate how vascular MR- induced TNF production impairs endothelial calcium signaling and elevates blood pressure in obesity. We will use smooth muscle cell-specific MR knockout mice to determine the role of smooth muscle MR in increasing TNF production and impairing endothelial function in obesity. Finally, we will determine the contribution of smooth muscle TRPV4 channels and related pathways in increasing TNF production in obesity. Studies in skeletal muscle arteries of obese patients will establish the clinical relevance of our findings on vascular MR-TNF-TNFRI signaling axis in obesity. Collectively, these fundamental and clinically relevant studies will fill major gaps in our understanding of endothelial calcium signaling abnormalities in obesity and identify potential therapeutic targets for rescuing endothelial function.
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