AMPK‐mediated prevention of vascular dysfunction with metformin: Experimental and population‐based evidence

Background and Purpose Metformin is increasingly recognised for its vasculoprotective effects, primarily through activation of AMP‐activated protein kinase (AMPK). We combined population‐based genetic epidemiology, with an ex vivo vascular model, to investigate the beneficial vascular effects of AMPK activation by metformin. Experimental Approach We used genetically proxied AMPK activation (GP‐AMPK), based on 20 genome‐wide significant single‐nucleotide polymorphisms (SNPs), to assess associations with pulse wave velocity (PWV) and carotid intima‐media thickness (cIMT). A two‐sample Mendelian randomisation (MR) was performed to test the effect of GP‐AMPK on a panel of inflammatory markers. We also developed a porcine coronary artery model of endothelial dysfunction to test the restorative effects of metformin on vascular function and related molecular signalling pathways. Key Results Higher GP‐AMPK activation was associated with lower PWV, but not cIMT, in our epidemiological analysis (mean age 64.3 years, 43.8% female). Ex vivo, metformin restored endothelial relaxation in Angiotensin (Ang) II–treated vessels via endothelium‐dependent hyperpolarisation (EDH) mechanisms, an effect abolished by AMPK inhibition. Western blotting confirmed the activation of AMPK (alpha 1 subunit) with metformin treatment. Inhibitor studies demonstrated a shift from NO‐mediated to EDH‐mediated relaxation with metformin. Molecular analyses showed reduced Ang II–induced expression of matrix remodelling (MMP1, MMP2) and senescence (P21) markers, as well as suppression of pro‐inflammatory cytokines (Il‐1β, Il‐6, TNF‐α), consistent with MR results. Conclusion and Implications Metformin restored endothelial function and reduced vascular stiffness through an AMPK–EDH axis, highlighting a novel, potential therapeutic mechanism for early vascular dysfunction independent of glycaemic effects.