Abstract P3015: Mechanosensitive, Piezo2 Channels Mediate The Exaggerated Exercise Pressor Reflex In A Mouse Model Of Hind Limb Ischemia.

Abstract

The exercise pressor reflex (EPR) is a reflexive mechanism in which blood pressure and heart rate increase in response to afferent neuron activation by skeletal muscle contraction. Patients with peripheral artery disease (PAD) have an exaggerated EPR, contributing to exercise intolerance, morbidity and mortality. Recently, we developed a mouse model which we used to determine the effect of femoral artery ligation (FAL) on the EPR. We observed that the EPR is exaggerated 72 hrs following FAL in mice. Stimulation of metabolically active afferent neurons was not different between FAL and control. In contrast, the responses induced by static contraction (stimulation of both mechanically and metabolically sensitive afferent fibers) and passive stretch (preferential stimulation of mechanically sensitive afferent neurons) were exaggerated in FAL mice when compared to control. These exaggerated responses were not affected by SB-705498 (a TRPv1 receptor inhibitor) but were nearly abolished by Gadolinium (a mechanical sensitive group III afferent neuron inhibitor) and significantly reduced by GsMTx-4 (a selective inhibitor of the PIEZO2 receptor).. Furthermore, we observed that PIEZO2 expression was upregulated in the dorsal root ganglia (DRG) from FAL mice compared to controls. Importantly, FAL mice displayed a decreased exercise capacity when compared to control mice, verifying that this mouse model mimics human PAD and supporting the notion that an exaggerated EPR contributes to exercise intolerance. These results further indicate that the exaggerated EPR in FAL is mediated, in part, by the PIEZO2 receptor. To explore this, we generated mice with a conditional, DRG targeted, deletion of Piezo2 . In these mice, we observed that the responses to static contraction and passive stretch were significantly reduced compared to control. Moreover, we performed whole-cell voltage-clamp on dissociated DRG observing increased negative pressure induced inward currents in the setting of FAL while these currents were decreased in the Piezo2 -/- DRG. These data indicate that PIEZO2 expression may serve as a therapeutic target in the treatment of PAD.