Increased TRPV4 channel expression enhances and impairs blood vessel function in hypertension

Zhang, Xun and Buckley, Charlotte and Lee, Matthew D. and Salaun, Christine and MacDonald, Margaret and Wilson, Calum and McCarron, John G. (2024) Increased TRPV4 channel expression enhances and impairs blood vessel function in hypertension. Hypertension. ISSN 1524-4563 (https://doi.org/10.1161/HYPERTENSIONAHA.124.23092)

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Abstract

Background: Endothelial cell TRPV4 channels provide a control point that is pivotal in regulating blood vessel diameter by mediating the Ca2+-dependent release of endothelial-derived vasoactive factors. In hypertension, TRPV4-mediated control of vascular function is disrupted but the underlying mechanisms, and precise physiological consequences remain controversial. Methods: Here, using a comprehensive array of methodologies, endothelial TRPV4 channel function was examined in intact mesenteric resistance arteries from normotensive WKY and hypertensive SHR rats. Results: Our results show there is a notable shift in vascular reactivity in hypertension, characterized by enhanced endothelium-dependent vasodilation at low levels of TRPV4 channel activation. However, at higher levels of TRPV4 activity, this vasodilatory response is reversed, contributing to the aberrant vascular tone observed in hypertension. The change in response, from dilation to constriction, was accompanied by a shift in intracellular Ca2+ signaling modalities arising from TRPV4 activity. Oscillatory TRPV4-evoked IP3-mediated Ca2+ release, which underlies dilation, decreased, while the contraction inducing sustained Ca2+ rise, arising from TRPV4-mediated Ca2+ influx, increased. Our findings also reveal that while the sensitivity of endothelial cell TRPV4 to activation was unchanged, expression of the channel is upregulated and IP3 receptors are downregulated in hypertension. Conclusions: These data highlight the intricate interplay between endothelial TRPV4 channel expression, intracellular Ca2+ signaling dynamics, and vascular reactivity. Moreover, the data support a new unifying hypothesis for the vascular impairment that accompanies hypertension. Specifically, that endothelial cell TRPV4 channels play a dual role in modulating blood vessel function in hypertension.

ORCID iDs

Zhang, Xun ORCID logoORCID: https://orcid.org/0000-0003-0790-4291, Buckley, Charlotte ORCID logoORCID: https://orcid.org/0000-0002-7961-4544, Lee, Matthew D. ORCID logoORCID: https://orcid.org/0000-0001-8265-382X, Salaun, Christine ORCID logoORCID: https://orcid.org/0000-0003-3002-6810, MacDonald, Margaret, Wilson, Calum ORCID logoORCID: https://orcid.org/0000-0003-2500-0632 and McCarron, John G. ORCID logoORCID: https://orcid.org/0000-0002-3302-3984;
CORE (COnnecting REpositories)