Ertugliflozin induces vasodilation by inhibiting AMPK-mediated mitochondrial fission in vascular smooth muscle cells

Eur J Pharmacol. 2025 Sep 5:1002:177784. doi: 10.1016/j.ejphar.2025.177784.

Jie Yan ¹, Xiaowen Zhang ², Lifeng Feng ², Shengzheng Zhang ³, Han Wei ², Wencong Tian ⁴, Qiwen Li ², Jing Li ², Liang Yang ⁵, Jie Liu ², Yang Xu ², Jianlin Cui ², Shan Ren ⁶, Zhi Qi ⁷, Yang Gao ⁸

Affiliations

1 Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, PR China; Laboratory & Equipment Management Department, Nankai University, Tianjin, 300071, PR China.
2 Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, PR China.
3 The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250033, PR China.
4 Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300122, PR China.
5 Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, PR China; Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300122, PR China.
6 The First Department of Critical Care Medicine, The First Affiliated Hospital of Shihezi University, Shihezi, 832003, PR China. Electronic address: newllyshan@163.com.
7 Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, PR China; The First Department of Critical Care Medicine, The First Affiliated Hospital of Shihezi University, Shihezi, 832003, PR China; Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300122, PR China; Core Laboratory, Beichen Hospital, Nankai University, Tianjin, 300071, PR China. Electronic address: qizhi@nankai.edu.cn.
8 Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, PR China; Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300122, PR China. Electronic address: gaoy@nankai.edu.cn.

PMID: 40451567 DOI: 10.1016/j.ejphar.2025.177784

Abstract

Hypertension is a primary risk factor for Cardiovascular Disease. Recently, Ertugliflozin (Ertu), a new sodium-glucose cotransporter-2 (SGLT2) inhibitor, though primarily approved by the FDA as an antidiabetic agent, has been reported to lower blood pressure. However, whether Ertu directly regulates the contractility of arteries remains unknown. Here, we examined Ertu's effects on vascular function and underlying molecular mechanisms. Isometric tension of arteries was recorded using a multi-wire myograph system. In rat mesenteric arteries, Ertu acutely relaxed vessels constricted by phenylephrine (PE) and high K⁺ (KPSS), while pretreatment with Ertu inhibited PE- and KPSS- induced vascular constriction. Similar outcomes were observed in the mouse thoracic aorta. Notably, these vasodilatory effects of Ertu are mediated by vascular smooth muscle cells (VSMCs) rather than endothelial cells. Mechanistically, we found that Ertu activated AMP-activated protein kinase (AMPK) signaling pathway in VSMCs and rat thoracic aorta tissues by decreasing ATP levels and the ATP/ADP ratio. Using the AMPK Inhibitor Compound C, we observed that Ertu-induced vasodilation was abolished. Furthermore, we found that Compound C reversed Ertu-mediated reductions in cytosolic calcium concentration ([CA²⁺]i) and mitochondrial fission, which were accompanied by diminished mitochondrial membrane potential in VSMCs. In conclusion, this study demonstrates for the first time that Ertu inhibits AMPK-mediated mitochondrial fission in VSMCs, leading to vasorelaxation, suggesting its potential as a therapeutic agent for hypertension.

Keywords

AMPK; Ertugliflozin; Mitochondrial fission; Smooth muscle cell; Vasodilation.

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Description

Target

Research Area
HY-15534

JC-1

99.0%, Mitochondrial Membrane Potential Probe

Fluorescent Dye

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