Activation of post-junctional neurotransmitter receptors in vascular smooth muscle cells modulates vascular tone and causes significant alterations in organ perfusion, mechanisms of which may be amplified or reduced in cardiovascular and renal disease. Neurotransmitter release from presynaptic nerve terminals is highly dependent on extracellular Ca2+ influx. Thus, modulation of Ca2+-permeable channels in neurons that impinge on microvessels can alter microcirculation by regulating neurotransmission. A large body of literature has elucidated the role of vascular smooth muscle and endothelial cell Ca2+ signaling in the control of microvascular function. However, there remains a significant knowledge gap on the function and pathophysiology of perivascular nerve ion channels in microcirculation. The current application stems from pilot studies that uncovered a new role for the transient receptor potential melastatin 8 (TRPM8) channels outside of sensory signaling. We propose an intriguing concept that a subset of peripheral sympathetic nerves (sn) expresses TRPM8 channels. Our data suggest that snTRPM8 is redox-sensitive and that the responses mediated by perivascular snTRPM8 channels alter vascular resistance via smooth muscle cell adrenergic system. We will use a repertoire of physiological; pharmacological; and high- content imaging approaches to study the central hypothesis that snTRPM8 activation increases vascular resistance and reduces vascular bed perfusion via Ca2+-dependent catecholamine neurotransmission and that this pathway contributes to oxidative stress-induced vascular dysfunction. To address this hypothesis, three specific aims will be investigated.
Aim 1 will test the hypothesis that perivascular snTRPM8 activation reduces microcirculation via sn-dependent vasoconstriction.
Aim 2 will study the hypothesis that redox-evoked snTRPM8 channel activation increases vascular resistance.
Aim 3 will explore the concept that snTRPM8-dependent sympathoexcitation contributes to oxyradical-induced vascular dysfunction and renal damage. This project will utilize selective pharmacological modulators of TRPM8 channels and mice with global and sn-specific TRPM8 deletion. Techniques to investigate microcirculation include transit-time ultrasound, laser-Doppler, and multiphoton microscopy.
Despite a plethora of treatment options, the burden of hypertension, stroke, myocardial infarction, and kidney failure still poses significant challenges to United States public health and economy. This proposal will uncover new insights into the mechanisms that control microvascular function and their roles in cardiovascular and kidney disorders, thereby providing potential therapeutic targets for the prevention or treatment of these life-threatening diseases.
