Activation of post-junctional neurotransmitter receptors in vascular endothelial and smooth muscle cells modulates
vascular tone and causes significant alterations in organ perfusion, mechanisms of which may be amplified or
diminished in cardiovascular and kidney 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 endothelial and smooth muscle Ca2+-permeable channels in the control of microvascular
function. However, the physiology and pathophysiology of perivascular nerve ion channels in microcirculation are
poorly understood. Accumulating evidence suggests that the transient receptor potential melastatin 8 (TRPM8), a
cold-sensitive neuronal channel may exert multiple functions in other cells and tissues, including blood vessels.
The current application stems from pilot studies that uncovered a new vascular role for TRPM8. Our data suggest
that a subset of perivascular sympathetic nerves (sn) expresses functional and redox-sensitive TRPM8 channels.
Hence, we propose to study the novel central hypothesis that snTRPM8 activation increases vascular resistance
and reduces vascular bed perfusion via Ca2+-dependent catecholamine exocytosis and that this pathway
contributes to the pathophysiology of reactive oxygen species in the vasculature. We will investigate whether: 1)
snTRPM8 channel activation impairs vascular bed perfusion by altering microvascular diameter and 2) TRPM8-
dependent sympathoexcitation contributes to oxidative stress-induced vascular dysfunction and kidney injury. This
project will utilize selective pharmacological modulators of TRPM8 channels, chemical sympathectomy, and
conditional and global TRPM8 knockout mouse models. Techniques to investigate microvascular function include
multiphoton microscopy, myography, transit-time ultrasound, and laser-Doppler.