Abstract P3134: Mechanosensitive Piezo2 Channel Mediates 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 skeletal muscle contraction. These reflexive increases are caused by both mechanical and metabolic stimulation of group III and IV afferent neurons innervating in contracting skeletal muscle. Patients with peripheral artery disease (PAD) have an exaggerated EPR which contributes to exercise intolerance and morbidity and mortality. Recently, we developed a mouse model of EPR, and have validated that the mouse model is similar to our rat model. With this mouse model of EPR, we studied the EPR following femoral artery ligation (FAL), briefly the right hind limb common femoral artery was ligated and transected between the proximal end near the groin and the distal end near the bifurcation of the popliteal artery and the saphenous artery. The same procedure was done without femoral artery ligation and transection for sham control. We observed that the mean arterial pressure (MAP) responses to ventral root stimulation (which excite metabo- and mechano-sensitive afferent neurons) and passive stretch (mechanosensitive stimulation only) were exaggerated 72 hours following FA ligation when compared to sham treated controls. The exaggerated EPR was significantly reduced by intra-arterial administration of Gadolinium (a mechanical sensitive group III afferent neurons inhibitor), GsMTx-4 (a selective Piezo2 inhibitor), but not by SB-705498 (a TRPv1 receptor inhibitor). Additionally, selective stimulation of metabolically sensitive afferent neurons by intra-arterial capsaicin injection (an activator of metabolically sensitive afferent neurons) induced equal, dose-related increases in MAP in both FA ligation and control mice. Finally, immunofluorescence staining visualized that the mechano-sensitive channel Piezo2 is localized in most large diameter neuron cells in mouse lumbar DRG. First, these results indicate that metabolically sensitive afferent neurons are not affected by FAL. Second, we observed that the exaggerated EPR in a murine model of PAD is mediated by mechanically sensitive group III neurons, which is due, in part, to Piezo2 receptor activation. Future studies will be aimed at interrogation of the mechanosensitive mechanisms that mediate this abnormal response to exercise in a model of PAD. The goal of these studies will be to determine molecular targets through which the exaggerated EPR can be normalized to allow for the prescription of exercise in PAD patients.