TRPV1 and the regulation of arterial tone

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Small resistance arterioles are the principal regulators of tissue blood flow and blood pressure. These vessels sense changes in circumferential tension and continuously adjust their caliber to help maintain tissue perfusion, a process termed “myogenic autoregulation”. Although, myogenic tone usually changes slowly in arterioles of the heart and skeletal muscle, the myogenic tone is very rapid. This speed allows these organs to regulate high flow rates (up to 85% of cardiac output) to maintain spatiotemporal perfusion. Further, in skeletal muscle, the arterial tone is quickly turned off (<1s) after an initial muscle contraction to allow increased blood flow (reactive hyperemia), and aid the transition from rest to exercise. Importantly, during heart disease, diabetes, sepsis and ageing, myogenic tone markedly declines, impairing hemodynamics, muscle performance and contributing to pathology. The underlying mechanisms that enable dynamic regulation of myogenic tone are unknown. In this proposal, we will explore a critical role for the heat-gated ion channel, TRPV1. Our preliminary data, using TRPV1 reporter mice and functional studies combined, show that TRPV1 channels specifically localize to the smooth muscle of arterioles in the heart, skeletal muscle and adipose. We hypothesize that TRPV1 serves as a transduction channel to confer dynamic myogenic tone in small arterioles. Specifically, we will test the proposal that TRPV1 integrates two distinct properties of blood flow, both mechanical stimuli downstream of mechanosensing GPCRs, and the local blood temperature. We propose 3 aims to test this innovative hypothesis and to understand the underlying mechanisms. (1) To test the hypothesis that TRPV1 is critical for dynamic myogenic tone in small arteries and mechanotransduction in arterial smooth muscle cells, (2) To test the hypothesis that PLC signaling and heat underlie TRPV1 myogenic tone, (3) To test the hypothesis that binding of PI(4,5)P2 enables persistent TRPV1 activation necessary for myogenic tone.