Exaggerated exercise pressor reflex in a mouse model of femoral artery ligation

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. Previous studies in our laboratory have demonstrated that the EPR is overactive in a rat model of heart failure similar to it is in human heart failure patients. We determined that this abnormality was initiated by a blunting of the metabolic component but maintained by the mechanosensitive component of the reflex. Recently, we developed a mouse model of EPR, and have validated that the mouse model is similar to our rat model. In this model, studied the EPR in a model of peripheral artery disease (PAD). Our current results demonstrated that the blood pressure increase induced by passive stretch was exaggerated in mice 72 hours following femoral artery ligation. This exaggerated rise in blood pressure was not affected by SB-705498 (a TRPv1 receptor inhibitor) but it was nearly abolished by Gadolinium (a mechanical sensitive group III afferent neurons inhibitor) and it was partially reduced by GsMTx-4 (a selective inhibitor of the Piezo2 receptor). These results indicate that the exaggerated EPR in a murine model of PAD is mediated by mechanically sensitive group III neurons, which is mediated, in part, by Piezo2 receptors.