TRPV1 expressed throughout the arterial circulation regulates vasoconstriction

The capsaicin receptor, TRPV1, is a key ion channel involved in inflammatory pain signaling. 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 TRPV1 and TRPV1-Cre:tdTomato combined with Ca imaging revealed specific localization of TRPV1 to smooth muscle of terminal arterioles in the heart, fat and skeletal muscle. Capsaicin evoked inward currents and raised intracellular Ca 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 blood flow. TRPV1 was also critical for the vasoconstriction triggered by lysophosphatidic acid, a bioactive lipid generated by platelets, atherogenic plaques and adipocytes. Pharmacologic and/or genetic disruption of TRPV1 abolished these effects of capsaicin and lysophosphatidic acid. Notably, ablation of sensory nerves did not affect the responses to capsaicin revealing a vascular smooth muscle-restricted signaling mechanism. Moreover, unlike in sensory nerves, TRPV1 function in arteries was resistant to activity-induced desensitization. Thus, TRPV1 activation in vascular myocytes of resistance arterioles enables a persistent depolarizing current leading to constriction of coronary, skeletal muscle, and adipose arterioles and a sustained increase in systemic blood pressure.