Objectives— E2 accelerates reendothelialization through estrogen receptor α (ERα), and we now aimed at defining the precise local and systemic cellular actors of this process.

Methods and Results— The respective roles of endothelial and hematopoietic targets of E2 were investigated in a mouse carotid injury model, using confocal microscopy, to follow endothelium repair. Grafting ERα^−/− mice with ERα^+/+ bone marrow (BM) was not sufficient to restore the accelerative effect of E2 on reendothelialization, demonstrating the necessary role of extrahematopoietic ERα. Using an endothelial-specific inactivation of ERα (Cre-Lox system), we showed that endothelial ERα plays a pivotal role in this E2 action. Conversely, in ERα^+/+ grafted with ERα^−/− BM, the E2 regenerative effect was abolished, demonstrating that ERα-expressing hematopoietic cells are also needed. As eNOS expression in BM was required for this action, both endothelial progenitor cells and platelets could be the hematopoietic targets that participate to this beneficial E2 effect.

Conclusions— We demonstrate that endothelial ERα plays a pivotal role in E2-mediated reendothelialization. However, endothelial targeting alone is not sufficient because the concomitant stimulation of a subpopulation of BM ERα is necessary. This cooperation should be taken into account in strategies aimed at optimizing in-stent reendothelialization.