Estrogen improves vascular function via peroxisome-proliferator-activated-receptor-γ.
The exact mechanism of estrogen in cardiovascular disease is not fully understood. As estrogen receptors (ERs), the peroxisome-proliferator-activated-receptor-γ (PPARγ) belongs to the family of ligand activated nuclear receptors regulating atheroprotective genes. The aim of this project was to investigate whether vascular effects of estrogen are mediated via PPARγ-regulation in the vascular compartment. Estrogen deficient ovariectomized wildtype-mice (OVX) displayed significant reduction of PPARγ-expression in aortic tissue compared to wildtype-mice with intact ovarian function (Sham). Hormone replacement with subdermal 17ß-estradiol pellets significantly increased vascular PPARγ-expression in ovariectomized female wildtype-mice (OVX/E2). Analogous to wildtype-mice, estrogen-deficient OVX ApoE(-/-)-mice had low vascular PPARγ-expression associated with ROS generation, endothelial dysfunction and atherogenesis. Estrogen replacement (OVX/E2) rescued vascular PPARγ-expression, reduced ROS generation, monocyte recruitment, atherosclerotic lesion formation and improved endothelial function. Inhibition of PPARγ by GW9662, a specific PPARγ-antagonist reduced 17ß-estradiol mediated vascular effects (OVX/E2+GW9662). Finally, despite estrogen deficiency treatment with pioglitazone (OVX+pioglitazone), a selective PPARγ-agonist, compensates deterioration of vascular morphology and function. 17ß-estradiol regulates vascular PPARγ-expression in wildtype- and ApoE(-/-)-mice. The presented data demonstrate the fundamental relevance of PPARγ as downstream target of 17ß-estradiol-related anti-inflammatory and atheroprotective effects within the vascular wall independent of its cardiovascular risk factor modifications.
Medizinische Klinik und Poliklinik II, Innere Medizin, Universitätsklinikum Bonn, Sigmund Freud Str. 25, 53105 Bonn, Germany.
Vedat
V
Tiyerili
Cornelius F H
CF
Müller
Stephen
S
Fung
Darius
D
Panek
Georg
G
Nickenig
Ulrich M
UM
Becher
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007150:Immunohistochemistry; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077205:Pioglitazone; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D001057:Apolipoproteins E; D004967:Estrogens; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D013481:Superoxides; D004958:Estradiol; D000077205:Pioglitazone