Aerobic Exercise Regulating Arterial Function by Lactate/GPR81 Signaling Pathway

G protein-coupled receptor 81 (GPR81) is a hydroxycarboxylic acid receptor that has been identified in recent years to be widely expressed in cells of a variety of tissues. It has been demonstrated that lactate (LA) is the sole endogenous, natural ligand for GPR81 under physiological conditions. However, the precise function of GPR81 in the regulation of arterial function remains to be elucidated. The present study constructed a mouse model of impaired arterial function by subjecting C57/BL6J female mice to a high-fat diet (HFD) and ovariectomy (OVX). The results demonstrated that mice with OVX and obesity exhibited increased arterial stiffness, accompanied by lipid metabolism disorder. Furthermore, a substantial quantity of oxidized low-density lipoprotein (ox-LDL) was observed in the aortic sinus region, which is a critical factor in the development of atherosclerosis. However, the 8-week aerobic exercise intervention was found to be capable of effectively reversing these adverse effects. Concurrently, in ovariectomized obese mice, serum LA levels exhibited a significant increase following exercise, as did the expression levels of aortic GPR81. Furthermore, an increase in cAMP-response element-binding protein 1 (CREB) phosphorylation was observed, which resulted in an enhancement of endothelial nitric oxide synthase (eNOS) expression. Finally, the study confirmed that exercise did not restore arterial function-related indices in ovariectomized obese Gpr81 knockout mice. Thus, it was determined that exercise may enhance arterial function through the LA/GPR81/p-CREB/CREB/eNOS signaling pathway.