Early Inactivation of Membrane Estrogen Receptor Alpha (ER alpha) Recapitulates the Endothelial Dysfunction of Aged Mouse Resistance Arteries

Flow-mediated dilation (FMD) of resistance arteries is essential for tissue perfusion but it decreases with ageing. As estrogen receptor alpha (Er alpha encoded by Esr1), and more precisely membrane ER alpha, plays an important role in FMD in young mice in a ligand-independent fashion, we evaluated its influence on this arteriolar function in ageing. We first confirmed that in young (6-month-old) mice, FMD of mesenteric resistance arteries was reduced in Esr1-/- (lacking ER alpha) and C451A-ER alpha (lacking membrane ER alpha). In old (24-month-old) mice, FMD was reduced in WT mice compared to young mice, whereas it was not further decreased in Esr1-/- and C451A-ER alpha mice. Markers of oxidative stress were similarly increased in old WT and C451A-ER alpha mice. Reduction in oxidative stress with superoxide dismutase plus catalase or Mito-tempo, which reduces mitochondrial superoxide restored FMD to a normal control level in young C451A-ER alpha mice as well as in old WT mice and old C451A-ER alpha mice. Estradiol-mediated dilation was absent in old WT mice. We conclude that oxidative stress is a key event in the decline of FMD, and that an early defect in membrane ER alpha recapitulates phenotypically and functionally ageing of these resistance arteries. The loss of this function could take part in vascular ageing.