Both Tamoxifen and Estradiol accelerate endothelial healing by targeting different sub-functions of ERa and distinct cell types in the arterial wall
Rationale: Tamoxifen prevents the recurrence of breast cancer and is also beneficial against bone demineralization and arterial diseases, as it acts as an Estrogen Receptor (ER) a antagonist in ER-positive breast cancers, whereas it mimics the protective action of 17ß-estradiol (E2) in other tissues such as arteries. However, the mechanisms of these tissue-specific actions remain unclear. Objective: Here we tested whether tamoxifen is able to accelerate endothelial healing and analyzed the underlying mechanisms. Methods and Results: Using three complementary mouse models of carotid artery injury, we demonstrated that both tamoxifen and estradiol accelerated endothelial healing, but only tamoxifen required the presence of the underlying medial smooth muscle cells. Chronic treatment with E2 and tamoxifen elicited differential gene expression profiles in the carotid artery. The use of transgenic models mouse targeting either whole ERa in a cell-specific manner or ERa subfunctions (membrane/extra-nuclear versus genomic/transcriptional) demonstrated that E2-induced acceleration of endothelial healing is mediated by membrane ERa in endothelial cells, while the effect of tamoxifen is mediated by the nuclear actions of ERa in smooth muscle cells. Conclusion: Whereas tamoxifen acts as an anti-estrogen and ERa antagonist in breast cancer, but also on the membrane ERa of endothelial cells, it accelerates endothelial healing through activation of nuclear ERa in smooth muscle cells, inviting to revisit the mechanisms of action of selective modulation of ERa. Overall design: carotids arteries mRNA profiles of 3 weeks treated wild type mice with estradiol or tamoxifen, were generated by deep sequencing using  Illumina NovaSeq sequencer