The Transient Receptor Potential Vanilloid 4 Channel and Cardiovascular Disease Risk Factors

Abstract

Vascular endothelial cells regulate arterial tone through the release of nitric oxide and other diffusible factors such as prostacyclin and endothelium derived hyperpolarizing factors. Alongside these diffusible factors, contact-mediated electrical propagation from endothelial cells to smooth muscle cells via myoendothelial gap junctions, termed endothelium-dependent hyperpolarization (EDH), plays a critical role in endothelium-dependent vasodilation in certain vascular beds. A rise in intracellular Ca2+ concentration in endothelial cells is a prerequisite for both the production of diffusible factors and the generation of EDH, and Ca2+ influx through the endothelial transient receptor potential vanilloid 4 (TRPV4) ion channel, a nonselective cation channel of the TRP family, plays a critical role in this process in various vascular beds. Emerging evidence suggests that the dysregulation of endothelial TRPV4 channels underpins endothelial dysfunction associated with cardiovascular disease (CVD) risk factors, including hypertension, obesity, diabetes, and aging. Because endothelial dysfunction is a precursor to CVD, a better understanding of the mechanisms underlying impaired TRPV4 channels could lead to novel therapeutic strategies for CVD prevention. In this mini review, we present the current knowledge of the pathophysiological changes in endothelial TRPV4 channels associated with CVD risk factors, and then explore the underlying mechanisms involved.

Genetic- and diet-induced ω-3 fatty acid enrichment enhances TRPV4-mediated vasodilation in mice

“…TRPV4 activation promotes vasodilation by increasing intracellular Ca 2+ , followed by the activation of Ca 2+ -activated potassium channels, nitric oxide release, and subsequent smooth muscle cell hyperpolarization ( Earley et al, 2005 , 2009 ; Kohler et al, 2006 ; Sonkusare et al, 2012 ). Several lines of evidence suggest that reduced TRPV4 expression and function underlie endothelial impairment associated with cardiovascular disease risk factors, including hypertension, obesity, diabetes, and aging ( Goto and Kitazono, 2021 ). For example, TRPV4 expression and function are markedly reduced in the endothelial cells of various vascular beds in rat models of aging and diabetes, as well as in mouse models of obesity-induced hypertension, where vasodilation is compromised ( Du et al, 2016 ; Ottolini et al, 2020 ; Shamsaldeen et al, 2020 ).…”

TRPV4 Channel–Regulated Microdomains Define a New Paradigm in Hypertension

“…6 Receptor-operated channels and TRP channels have also been implicated in abnormal calcium handling and vascular dysfunction in hypertension and other cardiovascular diseases. 7 The significance and clinical relevance of calcium channel activation are confirmed by the proven clinical success of L-type calcium channel blockers in the management of hypertension. These drugs target L-type CaV1.2 calcium channels, prevent VSMC calcium influx, and dampen procontractile signaling, with consequent decreased vascular contraction, increased vasodilation, and reduced blood pressure.…”

Role of TRP Channels in Metabolism-Related Diseases

“…According to reports, TRPV1 has the potential to facilitate UCP2-mediated endothelial dysfunction [117]. The dysregulation of the endothelial TRPV4 channel may be associated with endothelial cell dysfunction and may contribute to the onset and progression of cardiovascular diseases such as diabetes, hypertension, and obesity [118,119]. TRPV4 is involved in the endothelium-dependent vasodilation EDHF pathway in response to blood flow and acetylcholine (ACh) in endothelial cells.…”