Tamoxifen Accelerates Endothelial Healing By Targeting Er Alpha In Smooth Muscle Cells

RATIONALE: Tamoxifen prevents the recurrence of breast cancer and is also beneficial against bone demineralization and arterial diseases. It acts as an ER (estrogen receptor) alpha antagonist in ER-positive breast cancers, whereas it mimics the protective action of 17 beta-estradiol 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 3 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 17 beta-estradiol and tamoxifen elicited differential gene expression profiles in the carotid artery. The use of transgenic mouse models targeting either whole ER alpha in a cell-specific manner or ER alpha subfunctions (membrane/extranuclear versus genomic/transcriptional) demonstrated that 17 beta-estradiol-induced acceleration of endothelial healing is mediated by membrane ER alpha in endothelial cells, while the effect of tamoxifen is mediated by the nuclear actions of ER alpha in smooth muscle cells.CONCLUSIONS: Whereas tamoxifen acts as an antiestrogen and ER alpha antagonist in breast cancer but also on the membrane ER alpha of endothelial cells, it accelerates endothelial healing through activation of nuclear ER alpha in smooth muscle cells, inviting to revisit the mechanisms of action of selective modulation of ER alpha.