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ResearchIn-Press PreviewCardiologyEndocrinologyMetabolism Open Access | 10.1172/jci.insight.201148

Semaglutide Reduces Murine Blood Pressure Through the Vascular Smooth Muscle GLP-1 Receptor

Kyle D. Medak,1 Jacqueline A. Koehler,1 Laurie L. Baggio,1 Maria J. Gonzalez-Rellan,1 Chi Kin Wong,1 Xiemin Cao,1 Vivikta Rao,3 Sean Kao,3 Yu Cui,3 Jiayi Fu,3 Easton Liaw,3 M. Golam Kabir,1 Jie Zhang,3 Jin Wei,3 and Daniel J. Drucker1

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Medak, K. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Koehler, J. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Baggio, L. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Gonzalez-Rellan, M. in: PubMed | Google Scholar |

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Wong, C. in: PubMed | Google Scholar |

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Cao, X. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Rao, V. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Kao, S. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Cui, Y. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Fu, J. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Liaw, E. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Kabir, M. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Zhang, J. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Wei, J. in: PubMed | Google Scholar

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Spain

3Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, United States of America

Find articles by Drucker, D. in: PubMed | Google Scholar |

Published March 3, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.201148.
Copyright © 2026, Medak et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 3, 2026 - Version history
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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 pro-apoptotic signaling that are abolished in mice lacking VSMC GLP-1R expression. Moreover, semaglutide directly induced vasorelaxation in pre-constricted 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.

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