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: Marie-Cécile Valéra, Marie-Pierre Gratacap, Pierre Gourdy, Françoise Lenfant, Cendrine Cabou, Celine E Toutain, Marlene Marcellin, Nathalie Saint Laurent, Pierre Sié, Michel Sixou, Jean-François Arnal, Bernard Payrastre
• Journal: Blood (Blood) Vol. 120 Issue 8 Pg. 1703-12 (Aug 23 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22776819 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Receptor alpha
• Proteome
• Tubulin
• Estradiol

Topics

• Animals
• Bleeding Time
• Blood Platelets (cytology, drug effects)
• Estradiol (pharmacology, therapeutic use)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gene Deletion
• Hematopoietic Stem Cells (metabolism)
• Mice
• Mice, Inbred C57BL
• Ovariectomy
• Platelet Aggregation (drug effects)
• Proteome (metabolism)
• Thromboembolism (genetics, metabolism, prevention & control)
• Tubulin (metabolism)