Perinatal testosterone exposure potentiates vascular dysfunction by ERβ suppression in endothelial progenitor cells

• Published in: PloS one Vol. 12; no. 8; p. e0182945
• Main Authors: Xie, Weiguo, Ren, Mingming, Li, Ling, Zhu, Yin, Chu, Zhigang, Zhu, Zhigang, Ruan, Qiongfang, Lou, Wenting, Zhang, Haimou, Han, Zhen, Huang, Xiaodong, Xiang, Wei, Wang, Tao, Yao, Paul
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.08.2017; Public Library of Science (PLoS)
• Subjects: 17β-Estradiol; Aging; Aging (artificial); Androgens; Animals; Biology and Life Sciences; Biotechnology; Blotting, Western; Bone marrow; Bone marrow transplantation; Cardiovascular diseases; Cardiovascular system; Cells (biology); Childrens health; Chromatin Immunoprecipitation; Deoxyribonucleic acid; DNA; DNA Damage; DNA Methylation; Endothelial cells; Endothelial Progenitor Cells - drug effects; Endothelial Progenitor Cells - metabolism; Endothelium; Epigenetics; ERRalpha Estrogen-Related Receptor; Estradiol - pharmacology; Estrogen Receptor beta - genetics; Estrogen Receptor beta - metabolism; Estrogen receptors; Estrogens; Exposure; Fatty acids; Female; Geriatrics; Heart diseases; Heart surgery; Hypertension; Male; Maternal & child health; Medicine and Health Sciences; Men; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria; Offspring; Oxygen; Pediatrics; Perinatal exposure; Phosphorylation; Phosphorylation - drug effects; Proteins; Radioimmunoassay; Reactive oxygen species; Reactive Oxygen Species - pharmacology; Real-Time Polymerase Chain Reaction; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; RNA, Small Interfering - genetics; Senescence; Sex hormones; SIRT1 protein; Stem cell transplantation; Stem cells; Superoxide dismutase; Superoxide Dismutase - metabolism; Testosterone; Testosterone - pharmacology; Transplantation; Vascular system
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0182945

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 β (ERβ) suppression in endothelial progenitor cells (EPCs) in offspring but not mothers, while estradiol (E2) had no effect. Further investigation showed that ERβ suppression is due to perinatal testosterone exposure-induced epigenetic changes with altered DNA methylation on the ERβ promoter. During aging, EPCs with ERβ suppression mobilize to the vascular wall, differentiate into ERβ-suppressed mouse endothelial cells (MECs) with downregulated expression of SOD2 (mitochondrial superoxide dismutase) and ERRα (estrogen-related receptor α). 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 ERβ or a SIRT1 single mutant SIRT1-C152(D) that could modulate SIRT1 phosphorylation significantly ameliorated vascular dysfunction, while ERβ knockdown worsened the problem. We conclude that perinatal testosterone exposure potentiates vascular dysfunction through ERβ suppression in EPCs.