Tamoxifen prevents the recurrence of breast cancer and is also beneficial against bone demineralization and arterial diseases. Here, we tested whether tamoxifen can accelerate endothelial healing and analyzed the underlying mechanisms.
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. The use of transgenic mouse models targeting either whole ERα in a cell-specific manner or ERα subfunctions demonstrated that membrane ERα mediates 17β-estradiol-induced acceleration of endothelial healing in endothelial cells. In contrast, the effect of tamoxifen is mediated by the nuclear actions of ERα in smooth muscle cells.
In conclusion, the present study demonstrates that tamoxifen and E2 both accelerate endothelial healing through an ERα-dependent effect. These results should serve as a paradigm to revisit the action of estrogens and selective estrogen receptor modulators in breast cancer initiation and growth, angiogenesis, and immune surveillance but also arterial pathophysiology. Although successfully used for 40 years in medicine, understanding the mechanisms of action of tamoxifen is still in its beginning. Its arterial protective actions should be seriously considered in evaluating the benefit/risk ratio in breast cancer treatment.