Protective hematopoietic impact of estrogens in a mouse model of thrombosis: respective roles of nuclear vs membrane estrogen receptor alpha.
Fiche publication
Date publication
août 2015
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre
Tous les auteurs :
Valera MC, Fontaine C, Lenfant F, Cabou C, Guillaume M, Smirnova N, Kim SH, Chambon P, Katzenellenbogen JA, Katzenellenbogen BS, Payrastre B, Arnal JF
Lien Pubmed
Résumé
We recently reported that chronic 17beta-estradiol (E2) treatment in mice decreases platelet responsiveness, prolongs the tail-bleeding time and protects against acute thromboembolism via the hematopoietic estrogen receptor alpha (ERalpha) and independently of ERbeta. Here, we have explored the respective roles of membrane versus nuclear actions of ERalpha in this process, using: i) the selective activator of membrane ERalpha: estrogen dendrimer conjugate (EDC) and ii) mouse models with mutations in ERalpha. The selective targeting of activation function 2 of ERalpha (ERalpha-AF20 mouse) provides a model of nuclear ERalpha loss-of-function, while mutation of the ERalpha palmitoylation site (C451A-ERalpha mouse) leads to a model of membrane ERalpha deficiency. The combination of pharmacological and genetic approaches including hematopoietic chimera mice demonstrated that absence of either membrane or nuclear ERalpha activation in bone marrow does not prevent the prolongation of the tail-bleeding time, suggesting a redundancy of these two functions for this E2 effect. In addition, while hematopoietic membrane ERalpha is neither sufficient nor necessary to protect E2-treated mice from collagen/epinephrine-induced thromboembolism, the protection against death-induced thromboembolism is significantly reduced in the absence of hematopoietic nuclear ERalpha activation. Overall, this study emphasizes that hematopoietic cells (likely megakaryocytes and possibly immune cells) constitute an important target in the antithrombotic effects of estrogens, and delineate for the first time in vivo the respective roles of membrane vs nuclear ERalpha effects, with a prominent role of the latter.
Référence
Endocrinology. 2015 Aug 17:en20151522.