TRPV1 expressed throughout the arterial circulation regulates vasoconstriction and blood pressure

Abstract

Key points The functional roles of the capsaicin receptor, TRPV1, outside of sensory nerves are unclear. We mapped TRPV1 in the mouse circulation, revealing extensive expression in the smooth muscle of resistance arterioles supplying skeletal muscle, heart and adipose tissue. Activation of TRPV1 in vascular myocytes constricted arteries, reduced coronary flow in isolated hearts and increased systemic blood pressure. These functional effects were retained after sensory nerve ablation, indicating specific signalling by arterial TRPV1. TRPV1 mediated the vasoconstrictive and blood pressure responses to the endogenous inflammatory lipid lysophosphatidic acid. These results show that TRPV1 in arteriolar myocytes modulates regional blood flow and systemic blood pressure, and suggest that TRPV1 may be a target of vasoactive inflammatory mediators. Abstract The capsaicin receptor, TRPV1, is a key ion channel involved in inflammatory pain signalling. Although mainly studied in sensory nerves, there are reports of TRPV1 expression in isolated segments of the vasculature, but whether the channel localizes to vascular endothelium or smooth muscle is controversial and the distribution and functional roles of TRPV1 in arteries remain unknown. We mapped functional TRPV1 expression throughout the mouse arterial circulation. Analysis of reporter mouse lines TRPV1PLAP‐nlacZ and TRPV1‐Cre:tdTomato combined with Ca2+ imaging revealed specific localization of TRPV1 to smooth muscle of terminal arterioles in the heart, adipose tissue and skeletal muscle. Capsaicin evoked inward currents (current density ∼10% of sensory neurons) and raised intracellular Ca2+ levels in arterial smooth muscle cells, constricted arterioles ex vivo and in vivo and increased systemic blood pressure in mice and rats. Further, capsaicin markedly and dose‐dependently reduced coronary flow. Pharmacological and/or genetic disruption of TRPV1 abolished all these effects of capsaicin as well as vasoconstriction triggered by lysophosphatidic acid, a bioactive lipid generated by platelets and atherogenic plaques. Notably, ablation of sensory nerves did not affect the responses to capsaicin revealing a vascular smooth muscle‐restricted signalling mechanism. Moreover, unlike in sensory nerves, TRPV1 function in arteries was resistant to activity‐induced desensitization. Thus, TRPV1 activation in vascular myocytes enables a persistent depolarizing current, leading to constriction of coronary, skeletal muscle and adipose arterioles and a sustained increase in systemic blood pressure.

TRPV1 in arteries enables a rapid myogenic tone

“…permeability through TRPV1 activated by high concentrations of capsaicin is sufficient to constrict arterioles (Phan et al, 2020). Here we found that nifedipine completely inhibits myogenic tone, negating a contribution of Ca 2+ entry through TRPV1.…”

“…Recently, we performed functional mapping of TRPV1 throughout the mouse circulation. This analysis revealed extensive TRPV1 expression in the vascular smooth muscle of arterioles in the skeletal muscle, heart and adipose tissues (Phan et al, 2020).…”

“…Previously, we demonstrated prominent TRPV1 expression in arterioles supplying skeletal muscle, heart and adipose tissues (Phan et al, 2020). To identify potential physiological roles for TRPV1 in regulating vascular tone we tested the effects of the highly specific TRPV1 antagonists, BCTC and AMG517, in pressurized arterioles isolated from mouse skeletal muscle.…”

“…Recently, we performed functional mapping of TRPV1 throughout the mouse circulation. This analysis revealed extensive TRPV1 expression in the vascular smooth muscle of arterioles in the skeletal muscle, heart and adipose tissues (Phan et al , 2020). Furthermore, we found that activation of arteriolar TRPV1 channels by capsaicin or the endogenous lipid, LPA, markedly increased vascular tone and blood pressure (Phan et al , 2020).…”

“…This analysis revealed extensive TRPV1 expression in the vascular smooth muscle of arterioles in the skeletal muscle, heart and adipose tissues (Phan et al , 2020). Furthermore, we found that activation of arteriolar TRPV1 channels by capsaicin or the endogenous lipid, LPA, markedly increased vascular tone and blood pressure (Phan et al , 2020). Of note, the restricted expression of TRPV1 in small arterioles of skeletal muscle matches the classical studies mapping myogenic tone in the limb and skeletal muscle arterial tree (Uchida & Bohr, 1969).…”