Abstract
GLP-1 receptor (GLP-1R) agonists decrease blood glucose and body weight and reduce rates of cardiovascular and renal disease. Although GLP-1R activation lowers blood pressure (BP), the underlying mechanisms remain incompletely understood and have been attributed to weight loss and endothelial cell GLP-1R signaling. Here, we show that GLP-1Rs in vascular smooth muscle cells (VSMCs) are essential for semaglutide-mediated BP reduction in mice. In contrast, GLP-1Rs in Tie2+ endothelial or immune cells are not required for semaglutide to lower BP. The VSMC GLP-1R is dispensable for the effects of semaglutide on food intake, body weight, and blood glucose but is required for its actions to increase glomerular filtration rate and promote natriuresis. Systemic semaglutide administration resulted in proteomic changes in the renal artery and kidney in pathways related to platelet aggregation, fibrin clot formation, lipid metabolism, and proapoptotic signaling that are abolished in mice lacking VSMC GLP-1R expression. Moreover, semaglutide directly induced vasorelaxation in preconstricted mesenteric arteries ex vivo. Together, these findings identify VSMCs as a key cellular target linking GLP-1R activation to BP regulation, renal electrolyte excretion, and proteomic changes in renal artery and kidney.