Tie2-Cre–Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury

•Arg 263 on ERα (Arg 259 for human ERα) is a critical amino acid involved in the interaction with the p85α-subunit of PI3K and thus non-nuclear signaling.•Using the Cre-loxP system, a novel mouse model in which ERα non-nuclear signaling was inactivated in endothelial cells with intact nuclear function was generated.•Tie2-Cre–induced inactivation of ERα non-nuclear signaling abrogated the protection of estrogen against mechanical vascular injury, whereas it had a minimal impact on baseline cardiovascular and metabolic phenotypes.