Endothelial estrogen receptor {alpha} plays an essential role in the coronary and myocardial protective effects of estradiol in ischemia/reperfusion.
OBJECTIVE
To assess the coronary endothelial protective effects of 17β-estradiol (E2) and the role of estrogen receptor (ER) α in ischemia/reperfusion (I/R).


RESULTS
E2 exerts protective effects in cardiac I/R. However, the implication in vivo of the endothelium and the cellular targets of the anti-ischemic effects of E2 are unknown. Mice were subjected to I/R (30 minutes of I and 1 hour of R) in vivo, after which acetylcholine-induced relaxation of isolated coronary segments was assessed ex vivo. I/R induced a coronary endothelial dysfunction in untreated ovariectomized mice that was prevented by long-term treatment with E2 in wild-type, but not in ERα(-/-), mice. Chimeric mice inactivated for ERα in the hematopoietic compartment remained protected by E2. Further inactivation of endothelial ERα abolished the protective action of E2 on coronary endothelial function in Tie2-Cre(+) ERα(f/f) mice. More importantly, E2 significantly limited infarct size in wild-type mice but not in mice deficient in endothelial ERα, even in the presence of hematopoietic ERα.


CONCLUSIONS
Endothelial ERα plays a crucial role in the E2-induced prevention of endothelial dysfunction after I/R. To our knowledge, we demonstrate for the first time, by using unique genetically modified mice, that targeting endothelial protection per se can confer cardiomyocyte protection in I/R.
Favre
Julie
J
Department of Pharmacology, Institut National de la Santé et de la Recherche Médicale U644 and Rouen University Hospital, Institute for Biomedical Research Institut Fédératif de Recherches, University of Rouen, France.
Gao
Ji
J
Henry
Jean-Paul
JP
Remy-Jouet
Isabelle
I
Fourquaux
Isabelle
I
Billon-Gales
Audrey
A
Thuillez
Christian
C
Arnal
Jean-François
JF
Lenfant
Françoise
F
Richard
Vincent
V
D000818:Animals; D001794:Blood Pressure; D016026:Bone Marrow Transplantation; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D004958:Estradiol / Q000008:administration & dosage*; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015914:Estrogen Replacement Therapy; D005260:Female; D006339:Heart Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D018183:Transplantation Chimera; D014599:Uterus / Q000187:drug effects; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D004343:Drug Implants; D047628:Estrogen Receptor alpha; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D004958:Estradiol