Estrogen receptor alpha expression in both endothelium and hematopoietic cells is required for the accelerative effect of estradiol on reendothelialization.
OBJECTIVE
E2 accelerates reendothelialization through estrogen receptor alpha (ER alpha), and we now aimed at defining the precise local and systemic cellular actors of this process.


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 alpha(-/-) mice with ER alpha(+/+) bone marrow (BM) was not sufficient to restore the accelerative effect of E2 on reendothelialization, demonstrating the necessary role of extrahematopoietic ER alpha. Using an endothelial-specific inactivation of ER alpha (Cre-Lox system), we showed that endothelial ER alpha plays a pivotal role in this E2 action. Conversely, in ER alpha(+/+) grafted with ER alpha(-/-) BM, the E2 regenerative effect was abolished, demonstrating that ER alpha-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 alpha 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 alpha is necessary. This cooperation should be taken into account in strategies aimed at optimizing in-stent reendothelialization.
Toutain
Céline E
CE
Institut National de la Santé et de la Recherche Médicale, U858, IFR150, and Université de Toulouse III, Toulouse, France.
Filipe
Cédric
C
Billon
Audrey
A
Fontaine
Coralie
C
Brouchet
Laurent
L
Guéry
Jean-Charles
JC
Gourdy
Pierre
P
Arnal
Jean-François
JF
Lenfant
Françoise
F
D000818:Animals; D042783:Endothelial Cells / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000502:physiology*; D005260:Female; D006098:Granulocytes / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000502:physiology*; D019426:Integrases / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D042787:Receptor, TIE-2
D047628:Estrogen Receptor alpha; D004958:Estradiol; D052250:Nitric Oxide Synthase Type III; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C045073:Cre recombinase; D019426:Integrases