Estradiol mediates vasculoprotection via ERRα-dependent regulation of lipid and ROS metabolism in the endothelium.
The estrogen-mediated vasculoprotective effect has been widely reported in many animal studies, although the clinical trials are controversial and the detailed mechanisms remain unclear. In this study, we focused on the molecular mechanism and consequence of 17β-estradiol (E2)-induced ERRα (estrogen-related receptor alpha) expression in endothelium and its potential beneficial effects on vascular function. The human aorta endothelial cells were used to identify the detailed molecular mechanism and consequences for E2-induced ERRα expression through estrogen receptors (ER), where ERα responses E2-induced ERRα activation, and ERβ responses basal ERRα expression. E2-induced ERRα expression increases fatty acid uptake/oxidation with increased mitochondrial replication, ATP generation and attenuated reactive oxygen species (ROS) formation. We have obtained further in vivo proof from high-fat diet mice that the lentivirus-carried endothelium-specific delivery of ERRα expression on the vascular wall normalizes E2 deficiency-induced increased plasma lipids with ameliorated vascular damage. ERRα knockdown worsens the problem, and the E2 could only partly restore this effect. This is the first time we report the detailed mechanism with direct evidence that E2-induced ERRα expression modulates the fatty acid metabolism and reduces the circulating lipids through endothelium. We conclude that E2-induced ERRα expression in endothelium plays an important role for the E2-induced vasculoprotective effect.
School of Public Health, Guangdong Medical College, Dongguan 523808, China.
Huawen
H
Li
Internal Medicine of Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
Zhaoyu
Z
Liu
Department of Neurology, Wuhan No.1 Hospital, 215 Zhongshan Rd. Wuhan 430022, China.
Yulan
Y
Gou
School of Public Health, Guangdong Medical College, Dongguan 523808, China.
Haibing
H
Yu
Department of Cardiac Surgery, School of Health Science, University of Ioannina, Greece.
Stavros
S
Siminelakis
Department of Obstetrics and Gynecology of Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
Shixuan
S
Wang
School of Public Health, Guangdong Medical College, Dongguan 523808, China.
Danli
D
Kong
Institute of Environmental Medicine of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Yikai
Y
Zhou
Internal Medicine of Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
Zhengxiang
Z
Liu
School of Public Health, Guangdong Medical College, Dongguan 523808, China. Electronic address: gdmcsbd@163.com.
Yuanling
Y
Ding
School of Public Health, Guangdong Medical College, Dongguan 523808, China. Electronic address: dachun927@hotmail.com.
Dachun
D
Yao
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D004730:Endothelium, Vascular / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000008:administration & dosage*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D047629:Estrogen Receptor beta / Q000096:biosynthesis* / Q000235:genetics; D004967:Estrogens / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000235:genetics; D000097983:ERRalpha Estrogen-Related Receptor
D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor
Estrogen receptor; Fatty acid metabolism; Mitochondria; Reactive oxygen species; Vascular function