Protective hematopoietic effect of estrogens in a mouse model of thrombosis: Respective roles of nuclear versus membrane estrogen receptor α

Marie Cécile Valera, Coralie Fontaine, Françoise Lenfant, Cendrine Cabou, Maeva Guillaume, Natalia Smirnova, Sung Hoon Kim, Pierre Chambon, John A. Katzenellenbogen, Benita S. Katzenellenbogen, Bernard Payrastre, Jean François Arnal

Research output: Contribution to journalArticle

Abstract

We recently reported that chronic 17β-estradiol (E2) treatment in mice decreases platelet responsiveness, prolongs the tail-bleeding time and protects against acute thromboembolism via the hematopoietic estrogen receptor alpha (ERα), and independently of ERβ. Here, we have explored the respective roles of membrane vs nuclear actions of ERαin this process, using: 1) the selective activator of membrane ERα: estrogen dendrimer conjugate, and 2) mouse models with mutations in ERα. The selective targeting of activation function 2 of ERα provides a model of nuclear ERα loss-of-function, whereas mutation of the ERαpalmitoylation site leads to a model of membrane ERα deficiency. The combination of pharmacological and genetic approaches including hematopoietic chimera mice demonstrated that absence of either membrane or nuclear ERαactivation in bone marrow does not prevent the prolongation of the tail-bleeding time, suggesting a redundancy of thesetwofunctions for this E2 effect. In addition, although hematopoieticmembraneERα 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 ERαactivation. 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 ERα effects, with a prominent role of the latter.

Original languageEnglish (US)
Pages (from-to)4293-4301
Number of pages9
JournalEndocrinology
Volume156
Issue number11
DOIs
StatePublished - Nov 2015

ASJC Scopus subject areas

  • Endocrinology

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    Valera, M. C., Fontaine, C., Lenfant, F., Cabou, C., Guillaume, M., Smirnova, N., Kim, S. H., Chambon, P., Katzenellenbogen, J. A., Katzenellenbogen, B. S., Payrastre, B., & Arnal, J. F. (2015). Protective hematopoietic effect of estrogens in a mouse model of thrombosis: Respective roles of nuclear versus membrane estrogen receptor α. Endocrinology, 156(11), 4293-4301. https://doi.org/10.1210/en.2015-1522