机构：[1]Institute of Burns, Tongren Hospital of Wuhan University, Wuhan, P.R.China,[2]Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen, P.R.China,北京大学深圳医院深圳市康宁医院深圳医学信息中心[3]Department of Pediatrics, Maternal and Child Health Care Hospital of Hainan Province, Haikou, P.R.China,[4]Department of Geriatrics, National Key Clinical Specialty, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, P.R.China,[5]School of Life Sciences, Hubei University, Wuhan, P.R.China
Recent clinical cohort study shows that testosterone therapy increases cardiovascular diseases in men with low testosterone levels, excessive circulating androgen levels may play a detrimental role in the vascular system, while the potential mechanism and effect of testosterone exposure on the vascular function in offspring is still unknown. Our preliminary results showed that perinatal testosterone exposure in mice induces estrogen receptor beta (ER beta) suppression in endothelial progenitor cells (EPCs) in offspring but not mothers, while estradiol (E2) had no effect. Further investigation showed that ER beta suppression is due to perinatal testosterone exposure-induced epigenetic changes with altered DNA methylation on the ER beta promoter. During aging, EPCs with ER beta suppression mobilize to the vascular wall, differentiate into ER beta-suppressed mouse endothelial cells (MECs) with downregulated expression of SOD2 (mitochondrial superoxide dismutase) and ERR alpha (estrogen-related receptor a). This results in reactive oxygen species (ROS) generation and DNA damage, and the dysfunction of mitochondria and fatty acid metabolism, subsequently potentiating vascular dysfunction. Bone marrow transplantation of EPCs that overexpressed with either ER beta or a SIRT1 single mutant SIRT1-C152(D) that could modulate SIRT1 phosphorylation significantly ameliorated vascular dysfunction, while ER beta knockdown worsened the problem. We conclude that perinatal testosterone exposure potentiates vascular dysfunction through ER beta suppression in EPCs.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81501667]; Wuhan Science and Technology Innovation Project [2015070404010214, 2013061402010510]; Hubei Science & Technology Development Project [2016CFB589, 2016CFB473, 2013BCB018]; Guangdong Province Medical Technology Research Project [A2016145]; Shenzhen Municipal Health Bureau [201501023]; Shenzhen Municipal Science and Technology Innovation Project [JCYJ20150403091443327]
第一作者机构：[1]Institute of Burns, Tongren Hospital of Wuhan University, Wuhan, P.R.China,
共同第一作者：
通讯作者：
通讯机构：[1]Institute of Burns, Tongren Hospital of Wuhan University, Wuhan, P.R.China,[3]Department of Pediatrics, Maternal and Child Health Care Hospital of Hainan Province, Haikou, P.R.China,
推荐引用方式(GB/T 7714)：
Xie Weiguo,Ren Mingming,Li Ling,et al.Perinatal testosterone exposure potentiates vascular dysfunction by ER beta suppression in endothelial progenitor cells[J].PLOS ONE.2017,12(8):doi:10.1371/journal.pone.0182945.
APA：
Xie, Weiguo,Ren, Mingming,Li, Ling,Zhu, Yin,Chu, Zhigang...&Yao, Paul.(2017).Perinatal testosterone exposure potentiates vascular dysfunction by ER beta suppression in endothelial progenitor cells.PLOS ONE,12,(8)
MLA：
Xie, Weiguo,et al."Perinatal testosterone exposure potentiates vascular dysfunction by ER beta suppression in endothelial progenitor cells".PLOS ONE 12..8(2017)
