Background and PurposeMetformin, one of the most frequently prescribed medications for type 2 diabetes, reportedly exerts BP-lowering effects in patients with diabetes. However, the effects and underlying mechanisms of metformin on BP in non-diabetic conditions remain to be determined. The aim of the present study was to determine the effects of metformin on angiotensin II (Ang II) infusion-induced hypertension in vivo. Experimental ApproachThe effects of metformin on BP were investigated in wild-type (WT) C57BL/6J mice and in mice lacking AMP-activated protein kinase 2 (AMPK2) mice with or without Ang II infusion. Also, the effect of metformin on Ang II-induced endoplasmic reticulum (ER) stress was explored in cultured human vascular smooth muscle cells (hVSMCs). Key ResultsMetformin markedly reduced BP in Ang II-infused WT mice but not in AMPK2-deficient mice. In cultured hVSMCs, Ang II treatment resulted in inactivation of AMPK, as well as the subsequent induction of spliced X-box binding protein-1, phosphorylation of eukaryotic translation initiation factor 2 and expression of glucose-regulated protein 78kDa, representing three well-characterized ER stress biomarkers. Moreover, AMPK activation by metformin ablated Ang II-induced ER stress in hVSMCs. Mechanistically, metformin-activated AMPK2 suppressed ER stress by increasing phospholamban phosphorylation. Conclusion and ImplicationsMetformin alleviates Ang II-triggered hypertension in mice by activating AMPK2, which mediates phospholamban phosphorylation and inhibits Ang II-induced ER stress in vascular smooth muscle cells.