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The transient receptor potential vanilloid 4 (TRPV4) channel is a non-selective cation channel that is mostly permeable to calcium (Ca2+), which participates in intracellular Ca2+ handling in cardiac cells. It is widely expressed through the body and is activated by a large spectrum of physicochemical stimuli, conferring it a role in a variety of sensorial and physiological functions. Within the cardiovascular system, TRPV4 expression is reported in cardiomyocytes, endothelial cells (ECs) and smooth muscle cells (SMCs), where it modulates mitochondrial activity, Ca2+ homeostasis, cardiomyocytes electrical activity and contractility, cardiac embryonic development and fibroblast proliferation, as well as vascular permeability, dilatation and constriction. On the other hand, TRPV4 channels participate in several cardiac pathological processes such as the development of cardiac fibrosis, hypertrophy, ischemia–reperfusion injuries, heart failure, myocardial infarction and arrhythmia. In this manuscript, we provide an overview of TRPV4 channel implications in cardiac physiology and discuss the potential of the TRPV4 channel as a therapeutic target against cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The transient receptor potential vanilloid 4 (TRPV4) channel is a non-selective cation channel that is mostly permeable to calcium (Ca2+), which participates in intracellular Ca2+ handling in cardiac cells. It is widely expressed through the body and is activated by a large spectrum of physicochemical stimuli, conferring it a role in a variety of sensorial and physiological functions. Within the cardiovascular system, TRPV4 expression is reported in cardiomyocytes, endothelial cells (ECs) and smooth muscle cells (SMCs), where it modulates mitochondrial activity, Ca2+ homeostasis, cardiomyocytes electrical activity and contractility, cardiac embryonic development and fibroblast proliferation, as well as vascular permeability, dilatation and constriction. On the other hand, TRPV4 channels participate in several cardiac pathological processes such as the development of cardiac fibrosis, hypertrophy, ischemia–reperfusion injuries, heart failure, myocardial infarction and arrhythmia. In this manuscript, we provide an overview of TRPV4 channel implications in cardiac physiology and discuss the potential of the TRPV4 channel as a therapeutic target against cardiovascular diseases.

[Display omitted] • Capsaicin induced vasorelaxation of human colonic submucosal arterioles in vitro and in vitro. • Capsaicin induced an endothelium-dependent vasorelaxation of human submucosal arterioles. • Capsaicin induced an endothelium-dependent vasorelaxation of mouse mesenteric arterioles. • Capsaicin induced vasorelaxation minily by TRPV1-mediated endothelial nitric oxide release. • Capsaicin induced vasorelaxation mainly by TRPV4/endothelium-dependent hyperpolarization. • Capsaicin exerted anti-colitis action in wide-type mice, but not in TRPV4 knock-out mice. • Capsaicin rescued the impaired endothelium-dependent vasorelaxation via TRPV4/EDH pathway. Although capsaicin has long been used as food additive and medication worldwide, its actions on gastrointestinal tract as its most delivery pathway have not been well addressed. In the present study, we aimed to study GI actions of capsaicin on mesenteric arterioles in normal and colitis mice and to elucidate the underlying mechanisms. Vasorelaxation of human submucosal arterioles and the mesenteric arterioles from wide-type (WT) mice, TRPV1−/− and TRPV4−/− (KO) mice were measured. The expression and function of TRPV channels in endothelial cells were examined by q-PCR, immunostaining, Ca2+ imaging and membrane potential measurements. Capsaicin dose-dependently induced vasorelaxation of human submucosal arterioles and mouse mesenteric arterioles in vitro and in vivo through endothelium-dependent hyperpolarization (EDH), nitric oxide (NO), and prostacyclin (PGI 2). Using TRPV1 and TRPV4 KO mice, we found that capsaicin-induced vasorelaxation was predominately through TRPV4/EDH, but marginally through TRPV1/NO/PGI 2. Capsaicin induced hyperpolarization through activation of endothelial TRPV4 channels and intermediate-conductance of Ca2+-activated K+ channels to finally stimulate vasorelaxation. Importantly, capsaicin exerted anti-colitis action by rescuing the impaired ACh-induced vasorelaxation in WT colitis mice but not in TRPV4 KO colitis mice. Capsaicin increases intestinal mucosal blood perfusion to potentially prevent/treat colitis through a novel TRPV4/EDH-dependent vasorelaxation of submucosal arterioles in health and colitis. This study further supports our previous notion that TRPV4/EDH in mesenteric circulation plays a critical role in the pathogenesis of colitis. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. This study investigates the role of TRPV4 channels, which are transmembrane calcium channels that can regulate vascular tone, in modulating AAA formation. The elastase‐treatment model of AAA in C57BL6 (WT) mice and Angiotensin II treatment model in ApoE−/− mice were used to confirm our hypotheses. The administration of a specific TRPV4 antagonist, GSK2193874, in elastase‐treated WT mice and in AngII‐treated ApoE−/− mice caused a significant attenuation of aortic diameter, decrease in pro‐inflammatory cytokines (IL‐1β, IL‐6, IL‐17, MCP‐1, MIP‐1α, MIP‐2, RANTES, and TNF‐α), inflammatory cell infiltration (CD3 + T cells, macrophages, and neutrophils), elastic fiber disruption, and an increase in smooth muscle cell α‐actin expression compared to untreated mice. Similarly, elastase‐treated TRPV4−/− mice had a significant decrease in AAA formation, aortic inflammation, and vascular remodeling compared to elastase‐treated WT mice on Day 14. In vitro studies demonstrated that the inhibition of TRPV4 channels mitigates aortic smooth muscle cell‐dependent inflammatory cytokine production as well as decreases neutrophil transmigration through aortic endothelial cells. Therefore, our results suggest that TRPV4 antagonism can attenuate aortic inflammation and remodeling via decreased smooth muscle cell activation and neutrophil transendothelial migration during AAA formation. [ABSTRACT FROM AUTHOR]

Although absorbed NaCl increases intestinal blood flow to facilitate absorption and transportation, it is unclear if it can directly mediate mesenteric arterial relaxation. We aimed to investigate and test our hypothesis that Cl− induces mesenteric arterial vasorelaxation via endothelium-dependent hyperpolarization (EDH). We used wire myograph to study NaCl-induced vasorelaxation of mesenteric arteries isolated from mice. Cl−, Ca2+ and K+ imaging was performed in human vascular endothelial cells pre-treated with pharmacological agents. The Cl− concentration-dependently induced vasorelaxation of mesenteric arteries likely through EDH. The Cl−-induced vasorelaxation was attenuated in TRPV4 KO mice and inhibited by selective blockers of Na+-K+-2Cl− cotransporter 1 (NKCC1) (bumetanide, 10 μM), transient receptor potential vanilloid 4 (TRPV4) (RN-1734, 40 μM), and small conductance Ca2+-activated K+ channels (SK Ca) (apamin, 3 μM)/ intermediate conductance Ca2+-activated K+ channels (IK Ca) (TRAM-34, 10 μM) and myoendothelial gap junction (18α-glycyrrhetinic acid, 10 μM), but enhanced by a selective activator of IK Ca /SK Ca (SKA-31, 0.3 μM). Cl− decreased intracellular K+ concentrations in endothelial cells, which was reversed by apamin (200 nM) plus TRAM-34 (500 nM). Extracellular Cl− raised intracellular Cl− concentrations in endothelial cells, which was attenuated by bumetanide (10 μM). Finally, Cl− induced a transient Ca2+ signaling via TRPV4 in endothelial cells, which became sustained when the Ca2+ exit mode of Na+-Ca2+ exchanger (NCX) was blocked. Cl− induces a pure EDH-mediated vasorelaxation of mesenteric arteries through activation of endothelial NKCC1/TRPV4/NCX axis. We have provided a novel insight into the role of Cl−-induced vasorelaxation via EDH mechanism. [Display omitted] • NaCl directly induces vasorelaxation of mesenteric arterioles via Cl− entry. • Cl− entry via endothelial NKCC1 promotes Ca2+ entry via TRPV4 channels. • Cl− induces vasorelaxation through endothelial NKCC1/TRPV4/Ca2+/EDH pathway. [ABSTRACT FROM AUTHOR]