2. Academic Validation
  3. Novel mechanisms of metformin-induced vasorelaxation of mesenteric arterioles via endothelium-dependent hyperpolarization to treat murine colitis

Novel mechanisms of metformin-induced vasorelaxation of mesenteric arterioles via endothelium-dependent hyperpolarization to treat murine colitis

  • Eur J Pharmacol. 2025 Sep 15:1003:177900. doi: 10.1016/j.ejphar.2025.177900.
Luyun Zhang 1,  Zhiming Zhu 2,  Hui Dong 3
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Sichuan Provincial People's Hospital, Sichuan Academy of Medical Sciences, University of Electronic Science and Technology of China, Chengdu, 610072, China.
  • 2 Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing, China.
  • 3 Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao, 266073, China. Electronic address: donghui@qdu.edu.cn.
PMID: 40617384 DOI: 10.1016/j.ejphar.2025.177900
Abstract

Research purpose: Metformin, an FDA-approved medication for type 2 diabetes mellitus (T2DM), has been previously reported to have anti-colitis effects via anti-inflammatory, antioxidant, and gut microbiota modulation. However, the precise mechanisms of metformin-induced vasorelaxation in intestinal resistance vessels in health and ulcerative colitis (UC), remain largely unknown.

Materials and methods: Mulvany-style wire myograph was used to determine metformin-induced vasorelaxation of human submucosal arterioles and mesenteric arterioles from wild-type C57BL/6 mice and transient receptor potential vanilloid 4 knockout mice (TRPV4 KO mice). CA2+ imaging and patch clamp were applied in human umbilical vein endothelial cells (HUVEC). DSS-induced mouse UC model was used to examine the role of metformin-induced vasorelaxation in its anti-colitis effects.

Results: Metformin-induced vasorelaxation of human and mouse mesenteric arterioles through endothelium-dependent hyperpolarization (EDH) predominantly. Metformin induced endoplasmic reticulum (ER)/CA2+ release via PLC/IP3/IP3R pathway in HUVEC. Metformin also promoted CA2+ influx and membrane currents via store-operated CA2+ entry (SOCE) and TRPV4 channels. Metformin/EDH-mediated vasorelaxation almost remained intact in colitis while acetylcholine (ACh)/EDH-mediated vasorelaxation was almost impaired totally. Importantly, metformin/EDH-mediated vasorelaxation could rescue the impaired ACh/EDH-mediated vasorelaxation and ameliorate the destructive colitis mucosae.

Conclusions: Metformin/EDH-mediated vasorelaxation protects intestinal mucosae against colitis by rescuing the impaired ACh-induced vasorelaxation to recover mucosal hemoperfusion. We reveal an innovative action mode and underlying mechanisms of metformin on microvascular activities in health and colitis. Our data strongly suggest that metformin could be repurposed as a safe and effective medication to prevent/treat colitis, especially as a choice of drug for patients suffering from T2DM and UC.

Keywords

Endothelium-derived hyperpolarization; Metformin; Type 2 diabetes mellitus; Ulcerative colitis.

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