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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\u2010fat 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\u2010density lipoprotein (ox\u2010LDL) was observed in the aortic sinus region, which is a critical factor in the development of atherosclerosis. However, the 8\u2010week 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\u2010response element\u2010binding 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\u2010related indices in ovariectomized obese\n                    <jats:italic>Gpr81<\/jats:italic>\n                    knockout mice. Thus, it was determined that exercise may enhance arterial function through the LA\/GPR81\/p\u2010CREB\/CREB\/eNOS signaling pathway.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501374rr","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T13:41:21Z","timestamp":1758721281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Aerobic Exercise Regulating Arterial Function by Lactate\/GPR81 Signaling Pathway"],"prefix":"10.1096","volume":"39","author":[{"given":"Fengzhi","family":"Yu","sequence":"first","affiliation":[{"name":"The Key Laboratory of Adolescent Health Assessment and Exercise Intervention of the Ministry of Education East China Normal University  Shanghai People's Republic of China"},{"name":"School of Exercise and Health Shanghai University of Sport  Shanghai People's Republic of 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