Endothelial estrogen receptor-alpha plays a crucial role in the atheroprotective action of 17beta-estradiol in low-density lipoprotein receptor-deficient mice
| Autor: | Laurent Delpy, Coralie Fontaine, Jean-Charles Guéry, Audrey Billon-Galés, Bertrand Calippe, Victorine Douin-Echinard, Pierre Gourdy, Hortense Berges, Jean-François Arnal, Françoise Lenfant, Henrik Laurell |
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| Přispěvatelé: | Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
MESH: Integrases
Estrogen receptor 030204 cardiovascular system & hematology MESH: Mice Knockout MESH: Atherosclerosis Mice 0302 clinical medicine polycyclic compounds MESH: Animals Receptor MESH: Bone Marrow Transplantation MESH: Estrogen Receptor alpha Bone Marrow Transplantation Mice Knockout 0303 health sciences Estradiol Receptor TIE-2 medicine.anatomical_structure [SDV.IMM]Life Sciences [q-bio]/Immunology Female MESH: Receptor Protein-Tyrosine Kinases MESH: Endothelium Vascular MESH: Estradiol Cardiology and Cardiovascular Medicine hormones hormone substitutes and hormone antagonists medicine.medical_specialty Endothelium medicine.drug_class MESH: Mice Transgenic Transgene Ovariectomy MESH: Ovariectomy Mice Transgenic Biology 03 medical and health sciences Physiology (medical) Internal medicine medicine Animals MESH: Mice 030304 developmental biology Integrases Estrogen Receptor alpha Receptor Protein-Tyrosine Kinases Atherosclerosis Disease Models Animal Endocrinology Receptors LDL Estrogen MESH: Receptors LDL LDL receptor Endothelium Vascular MESH: Disease Models Animal MESH: Female Lipoprotein Hormone |
| Zdroj: | Circulation Circulation, American Heart Association, 2009, 120 (25), pp.2567-76. ⟨10.1161/CIRCULATIONAHA.109.898445⟩ |
| ISSN: | 0009-7322 1524-4539 |
| DOI: | 10.1161/CIRCULATIONAHA.109.898445⟩ |
| Popis: | Background— The prevention of early atheroma by estrogens has been clearly demonstrated in all animal models and appears to be mediated through a direct action on the arterial wall rather than through an effect on the lipoprotein profile. The goal of the present study was to evaluate which cellular target is crucial in this beneficial action of estradiol. Methods and Results— We first confirmed the key role of estrogen receptor-α (ERα) in the atheroprotective effect of estradiol, because this action was completely abolished in mice deficient in both the low-density lipoprotein receptor (LDLr) and ERα. Second, using chimeric mice with an ERα deficiency in the hematopoietic lineage, we showed the persistence of the protective action of estradiol, which suggests the involvement of extrahematopoietic ERα. Third, we showed that loxP-flanked ERα mice (ERα flox/flox ) bred with Tie2-Cre + mice on an LDLr −/− background had complete inactivation of ERα in most hematopoietic and all endothelial cells. Remarkably, in this mouse model, the atheroprotective effect of estradiol was completely abolished. Fourth, the atheroprotective effect of estradiol remained abolished in Tie2-Cre + ERα flox/flox LDLr −/− mice transplanted with either Tie2-Cre + ERα flox/flox or ERα −/− bone marrow, whereas it was present in analogous chimeric Tie2-Cre − ERα flox/flox LDLr −/− receivers expressing endothelial ERα. Conclusions— We demonstrate directly and for the first time that endothelial ERα represents a key target of the atheroprotective effect of estradiol, whereas hematopoietic ERα is dispensable. Selective estrogen receptor modulators that mimic the endothelial action of estradiol should now be considered in atheroprotection. |
| Databáze: | OpenAIRE |
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