期刊
JOURNAL OF PHYSIOLOGY-LONDON
卷 598, 期 24, 页码 5639-5659出版社
WILEY
DOI: 10.1113/JP279909
关键词
blood pressure; capsaicin; lysophosphatidic acid; TRPV1; vascular smooth muscle
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK-101040]
- Hungarian Research Fund [OTKA K116940]
- European Union
- European Regional Development Fund
- Gedeon Richter Talentum Foundation (Budapest, Hungary)
- [GINOP-2.3.2-15-2016-00043]
- [GINOP-2.3.2-15-2016-00050]
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. 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 TRPV1(PLAP-nlacZ)and TRPV1-Cre:tdTomato combined with Ca(2+)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 similar to 10% of sensory neurons) and raised intracellular Ca(2+)levels in arterial smooth muscle cells, constricted arteriolesex vivoandin vivoand 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.
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