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Background and introduction The difference in cardiovascular disease risk between age-matched women and men narrows as transition through menopause in observational studies. Estrogen exerts complex physiological effects via its non-nuclear and nuclear actions. Experimental studies have shown that endothelial estrogen receptors mediate vasoprotection via endothelial nitric oxide production, reendothelialization, and atherosclerosis. Prior studies in vitro addressed estrogen's effects on endothelial cells and vascular smooth muscle cells, leading to vasoprotection. However, the in vivo evidences are lacking for beneficial effects of endothelium non-nuclear ERα signaling on vascular remodelling in response to injury. Purpose This study aims to clarify the impact of endothelial ERα non-nuclear signaling in the vasoprotection, using a novel mouse model lacking tissue-specific ERα non-nuclear signaling. Methods We identified the amino acids of ERα which were responsible for its binding to p85α subunit of phosphatidylinositol 3-kinase in vitro. We generated a novel mouse model in which non-nuclear signaling of ERα was ablated in endothelial cells by crossing Tie2-Cre transgenic mice with floxed ERα mutants (RR259/260AA) in which p85α and ERα interaction was disrupted. Results In endothelial cells isolated from ERαKI/KITie2 cre/+ animals, E2 failed to induce phosphorylation of Akt, confirming the absence of ERα non-nuclear signaling. Baseline characteristics at 8 to 12 weeks of age were undistinguishable between the genotypes, including body weight, systolic blood pressure, uterine weight and echocardiographic fractional shortening. We then assessed how vascular remodelling process was impacted in a carotid artery wire injury model. Histological analyses with Elastica van Gieson staining two weeks after injury revealed that estrogen dependent suppression of remodelling response (intima to medial ratio) was abolished in ERαki/kiTie2cre/+mice (P=0.0004). Masson's Trichrome staining showed that in the presence of E2 fibrosis was significantly higher in ERαki/kiTie2cre/+ mice than ERαki/kiTie2cre/− mice (P=0.0015). Conclusions We generated a novel mouse model for tissue-specific ablation of ERα non-nuclear signaling by interfering ERα-PI3K interaction. Our results demonstrate that the pivotal role for ERα non-nuclear signaling of endothelial cells in carotid arterial protection following injury with its minimal impact on baseline cardiovascular phenotype. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Japan Heart Foundation Research Grant, SENSHIN Medical Research Foundation

Endothelial-specific Ablation of Non-nuclear Estrogen Receptor alpha Signaling Deteriorates Vascular Remodelling Response