Estrogen Receptor‐Alpha Activation of AMPK in Vascular Smooth Muscle Cells and Vascular Tone

The cardioprotective effects of estrogen have long been known to result, in part, from its influence on vascular tone. The classical ERs, ERalpha (ERα) and ERbeta (ERβ), can localize within the cell and function as ligand‐activated transcription factors, modulating gene expression in response to estrogen. ERα and ERβ can also localize to the plasma membrane and participate in rapid cellular activation by interacting with cellular signaling pathways. Estrogen has been shown to activate AMPK‐activated protein kinase (AMPK), suggesting that AMPK may mediate some of the effects of estrogen, including its influence on vascular tone. In this study, the selective ERα agonist 4,4′,4′‐(4‐propyl‐[1H]‐pyrazole‐1,3,5‐triyl)trisphenol (PPT), AMPK activators 5‐aminoimidazole‐4‐carboxamide (AICAR) and metformin, and the AMPK inhibitor Compound C were used to examine the importance of ERα‐AMPK signaling in the relaxation of aortic rings from male and female C57BL/6 mice. The results suggest that activation of AMPK represents a novel pathway through which ERα affects vasomotor tone. ( Supported by 5K12HD043451 ).