Signaling pathways regulating mechanoreflex sensitization in cardiovascular disease

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PROJECT SUMMARY Hallmark features of many forms of cardiovascular disease include exercise intolerance and a high risk of suffering an adverse ischemic cardiovascular event such as cardiac fibrillation, myocardial infarction, or stroke during physical exertion. An exaggerated increase in sympathetic nervous system activity during exercise (i.e., sympathoexcitation) is a direct contributor to exercise intolerance and the risk of such adverse events. During exercise, mechanical forces associated with contracting skeletal muscles stimulate small diameter muscle sensory neurons (group III/IV muscle afferents) which plays an integral role in the activation of a reflex, the exercise pressor reflex, that contributes to increased sympathetic nervous system activity during exercise. The goal of this project is to investigate the cellular signaling mechanisms that result in exaggerated mechanically- activated exercise pressor reflex sympathetic control signals in cardiovascular disease. Specifically, we will use a rat model of limb ischemia in which a femoral artery is chronically ligated (a model of simulated peripheral artery disease) and a complementary blend of molecular and whole-animal approaches to investigate the signaling pathways within muscle sensory neurons that result in a pathophysiological enhancement of mechanically-activated channel function. The incorporation of multiple experimental techniques including molecular, electrophysiology, reflex, and conscious exercise experiments will ensure that our findings are robust, integrative, and translational in nature. In Aim 1, we will investigate the role played by inositol 1,4,5-trisphosphate (IP3) receptors and altered calcium signaling in group III/IV muscle afferents in the exaggerated mechanical component of the exercise pressor reflex (i.e., the mechanoreflex) in rats with chronic limb ischemia. In Aim 2, we will investigate the role played by exchange protein activated by cAMP (EPAC), especially EPAC 1, signaling in group III/IV muscle afferents in the exaggerated mechanoreflex in rats with chronic limb ischemia. In Aim 3, we will investigate the role played by protein kinase C (PKC), especially PKCε, signaling in group III/IV muscle afferents in the exaggerated mechanoreflex in rats with chronic limb ischemia. This project is innovative because it is the first to systematically investigate the signaling mechanisms that modulate the function of mechanically activated channels that contribute to sympathoexcitation during exercise in cardiovascular disease. This project is significant because the experiments may identity three novel targets (IP3 receptors, EPAC1, and PKCε) for therapies aimed at mitigating sympathoexcitation, exercise intolerance, and/or elevated risk of ischemic events in cardiovascular disease patients.