Peripheral artery disease (PAD) is a common vascular disease that currently affects >10 million people in the
U.S. and >200 million people worldwide. PAD prevalence and incidence are sharply age-related and with our
national population ever aging, we will see a huge rise of PAD diagnoses. PAD refers to atherosclerotic occlusion
of vessels supplying lower extremities creating an ischemic environment during exercise. The ischemic
environment causes intermittent pain (i.e., claudication) and exercise intolerance. Along with pain, these patients
experience exaggerated increases in blood pressure which increase their risk of suffering an adverse ischemic
event in the form of cardiac fibrillation and/or stroke. Patients are frequently advised to avoid strenuous physical
activity, however, a marked increase in blood pressure occurs during even low intensity walking exercise.
The exercise pressor reflex, a feedback neural control mechanism activated by the mechanical and metabolic
signals associated with skeletal muscle contraction, contributes importantly to autonomic and cardiovascular
adjustments during exercise. This reflex is exaggerated in PAD and multiple lines of evidence indicate that the
mechanical portion of the reflex (i.e., the mechanoreflex) specifically underlies that exaggeration. Thus, the
mechanoreflex contributes to exaggerated increases in blood pressure and exercise intolerance in PAD patients.
The overall goal of the experiments proposed is to uncover the mechanisms of mechanoreflex
exaggeration in PAD. I plan to use the decerebrate, unanaesthetized rat model of simulated PAD in which a
femoral artery is ligated for ~72 hours. To isolate the mechanical from the metabolic signals associated with
skeletal muscle contraction, I use a 30 s dynamic passive hindlimb skeletal muscle stretch protocol which mimics
the exaggerated mechanoreflex in PAD patients. My preliminary data indicates that the thromboxane A2
receptors (TxA2-R) located on the sensory endings of skeletal muscle afferents plays a role in the
exaggerated mechanoreflex. TxA2-R are Gq-protein coupled receptors that signal the formation of inositol
triphosphate 3 (IP3) which plays a major role in intracellular signaling. While this second messenger pathway is
well defined in isolated neurons and in the chronic pain response seen in rodent models of pain, it has not been
investigated in our field of blood pressure regulation during exercise. My aim is to target IP3 receptors within
skeletal muscle sensory neurons to determine the role of second messenger signaling in the
exaggerated blood pressure response during mechanoreflex activation in a rat model of PAD.
The proposed experiments will enhance our understanding of second messenger signaling within sensory
neurons that will provide the foundation for the future development of specific therapeutic targets to improve
cardiovascular and autonomic function during physical activity and exercise in PAD patients.