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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1543.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Estrogen Receptor Expression in Both Endothelium and Hematopoietic Cells Is Required for the Accelerative Effect of Estradiol on Reendothelialization

Céline E. Toutain; Cédric Filipe; Audrey Billon; Coralie Fontaine; Laurent Brouchet; Jean-Charles Guéry; Pierre Gourdy; Jean-François Arnal; Françoise Lenfant

From the Institut National de la Santé et de la Recherche Médicale (INSERM) (C.E.T., C.F., A.B., C.F., L.B., P.G., J.-F.A., F.L.), U858, IFR150, and Université de Toulouse III, Toulouse, France; INSERM U563 (J.-C.G.), Centre de Physiopathologie de Purpan, Toulouse, France; and CHU de Toulouse (L.B., P.G., J.-F.A.), France.

Correspondence to Françoise Lenfant, Institut National de la Santé et de la Recherche Médicale (INSERM), U858, IFR150, and Université de Toulouse III, Toulouse, France. E-mail francoise.lenfant{at}inserm.fr

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^–/– mice with ER^+/+ 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^+/+ grafted with ER^–/– 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.

Perivascular carotid injury model associated with "en face" confocal microscopy allowed to demonstrate that endothelial ER is a key target in reendothelialization. Moreover, resident endothelial cells need to cooperate with bone marrow cells for the accelerative effect of estradiol on endothelial repair.

Key Words: estradiol • reendothelialization • carotid injury model • endothelium • confocal microscopy