Protective Hematopoietic Effect of Estrogens in a Mouse Model of Thrombosis: Respective Roles of Nuclear Versus Membrane Estrogen Receptor α.

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 ERα in 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 ERα palmitoylation 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 ERα 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, although hematopoietic membrane ERα 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 ERα 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 ERα effects, with a prominent role of the latter.

• Authors: Marie-Cécile Valéra, 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
• Journal: Endocrinology (Endocrinology) Vol. 156 Issue 11 Pg. 4293-301 (Nov 2015) ISSN: 1945-7170 [Electronic] United States
• PMID: 26280130 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Receptor alpha
• Estrogens

Topics

• Animals
• Cell Membrane (metabolism)
• Cell Nucleus (metabolism)
• Disease Models, Animal
• Estrogen Receptor alpha (genetics, metabolism)
• Estrogens (therapeutic use)
• Mice
• Mice, Transgenic
• Thrombosis (drug therapy, metabolism)