TRPV1 and the regulation of arterial tone

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.

Grant Number: 5R01HL155979-04
NIH Institute/Center: NIH
Principal Investigator: GERARD AHERN