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Objectives-E2 accelerates reendothelialization through estrogen receptor ␣ (ER␣), 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 ER␣ Ϫ/Ϫ mice with ER␣ ϩ/ϩ bone marrow (BM) was not sufficient to restore the accelerative effect of E2 on reendothelialization, demonstrating the necessary role of extrahematopoietic ER␣. Using an endothelial-specific inactivation of ER␣ (Cre-Lox system), we showed that endothelial ER␣ plays a pivotal role in this E2 action. Conversely, in ER␣ ϩ/ϩ grafted with ER␣ Ϫ/Ϫ BM, the E2 regenerative effect was abolished, demonstrating that ER␣-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 ER␣ plays a pivotal role in E2-mediated reendothelialization. However, endothelial targeting alone is not sufficient because the concomitant stimulation of a subpopulation of BM ER␣ is necessary. This cooperation should be taken into account in strategies aimed at optimizing in-stent reendothelialization. Key Words: estradiol Ⅲ reendothelialization Ⅲ carotid injury model Ⅲ endothelium Ⅲ confocal microscopy A ngioplasty followed by stent implantation is a commonly used procedure to treat coronary or peripheral artery stenosis. The major complication of bare metal stent implantation is intrastent stenosis because of neointimal hyperplasia. Drug-eluting stents have emerged as a potential solution against restenosis, 1 but they also inhibit proliferation of endothelial cells. Late thrombosis has become a major concern, because delayed arterial healing, characterized by incomplete reendothelialization, constitutes an important underlying substrate for coagulation. 2,3 Endothelium constitutes an antithrombogenic layer and limits neointima formation, and optimization of endothelial healing should be considered of primary importance. 4 Various treatment strategies to promote endothelial regrowth after arterial injury have been proposed. 5 Administration of angiogenic growth factors such as vascular endothelial growth factor 6 and fibroblast growth factor-2 (FGF-2) 7 increased endothelial healing in animal models. Endogenous mobilization or injection of ex vivo expanded endothelial progenitor cells (EPCs) was associated with enhanced reendothelialization. 8 Pharmacological agents including angiotensin-converting enzyme inhibition, 9 statins, 8,10 and estrogens 11,12 promote endothelial healing.17␤-estradiol (E2), the main endogenous estrogen, exerts many vascular protective effects by increasing basal production of endothelial nitric oxide (NO), 13 accelerating reendothelialization 12,14 or inhibiting neointima formation. 15 We previously demons...