title: Chronic estradiol treatment reduces platelet responses and protects mice from thromboembolism through the hematopoietic estrogen receptor α.
abstract: Although estrogens are known to have a deleterious effect on the venous thrombosis risk and a preventive action on the development of arterial atheroma, their effect on platelet function in vivo remains unclear. Here, we demonstrate that a chronic high physiologic level of estradiol (E2) in mice leads to a marked decrease in platelet responsiveness ex vivo and in vivo compared with ovariectomized controls. E2 treatment led to increased bleeding time and a resistance to thromboembolism. Hematopoietic chimera mice harboring a selective deletion of estrogen receptors (ERs) α or β were used to demonstrate that the effects of E2 were exclusively because of hematopoietic ERα. Within ERα the activation function-1 domain was not required for resistance to thromboembolism, as was previously shown for atheroprotection. This domain is mandatory for E2-mediated reproductive function and suggests that this role is controlled independently. Differential proteomics indicated that E2 treatment modulated the expression of platelet proteins including β1 tubulin and a few other proteins that may impact platelet production and activation. Overall, these data demonstrate a previously unrecognized role for E2 in regulating the platelet proteome and platelet function, and point to new potential antithrombotic and vasculoprotective therapeutic strategies.
authors: Inserm, U1048 and Université Toulouse 3, I2MC, Toulouse, France.
authors: Marie-Cécile
authors: MC
authors: Valéra
authors: Marie-Pierre
authors: MP
authors: Gratacap
authors: Pierre
authors: P
authors: Gourdy
authors: Françoise
authors: F
authors: Lenfant
authors: Cendrine
authors: C
authors: Cabou
authors: Celine E
authors: CE
authors: Toutain
authors: Marlene
authors: M
authors: Marcellin
authors: Nathalie
authors: N
authors: Saint Laurent
authors: Pierre
authors: P
authors: Sié
authors: Michel
authors: M
authors: Sixou
authors: Jean-François
authors: JF
authors: Arnal
authors: Bernard
authors: B
authors: Payrastre
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D010974:Platelet Aggregation / Q000187:drug effects*; D020543:Proteome / Q000378:metabolism; D013923:Thromboembolism / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D014404:Tubulin / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D020543:Proteome; D014404:Tubulin; D004958:Estradiol