Female-Specific Muscle Afferent Mechanisms in Abnormal Exercise Pressor Reflex After Ischemia-Reperfusion Injury

Peripheral artery disease (PAD) affects more than 200 million adults worldwide, yet women often experience worse outcomes than men. Many women do not feel the “typical” warning signs of PAD, such as leg pain during exercise. This delay in symptom recognition contributes to later diagnosis, reduced physical function, and higher risks of limb amputation. Hormonal decline during menopause may switch the sensory pathways that help detect ischemia and regulate cardiovascular responses during physical activity. My prior AHA Career Development Award established that ischemia-reperfusion (IR) injury sensitizes muscle afferent neurons and exaggerates the exercise pressor reflex (EPR), a neural mechanism that raises blood pressure during exercise. This exaggerated EPR may contribute to exercise intolerance and cardiovascular risk in PAD. However, these studies did not address the influence of estrogen deficiency, a major physiological change in women with PAD. My ongoing Junior Faculty Development Program (JFDP) project provides new insight into this gap. Pilot data show that ovariectomy (OVX), a model of estrogen loss, reduces the expression of ASIC1a and ASIC3, receptors expressed in CGRP-positive neurons in muscle afferent dorsal root ganglia. Interestingly, there was an increase in P2X3, a receptor expressed in IB4-binding neurons in OVX rats, suggesting a potential shift from CGRP-positive to IB4-positive sensory neurons following OVX. This switch may blunt the ability to sense ischemic-reperfusion muscle stress while altering reflexive cardiovascular responses. This Bridge Grant will integrate findings from the CDA and JFDP by determining how estrogen deficiency and sensory-neuron phenotype shifts affect the EPR after IR injury. Using OVX, OVX + estrogen replacement, and sham female rats, we will measure sensory neuron protein expression, calcium activity, and whole-animal cardiovascular responses during muscle contraction following IR. We hypothesize that the combination of decreased CGRP expression and increased IB4-binding neurons contributes to an abnormal, dysregulated EPR in estrogen-deficient females. This project directly addresses a significant gap in women’s cardiovascular health. The findings will provide essential pilot data for a future NIH R01 focused on hormone-dependent sensory mechanisms and support the development of diagnostic and therapeutic strategies tailored to PAD women.