期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 316, 期 5, 页码 E794-E809出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00359.2018
关键词
angiogenesis; mitochondrial homeostasis; Nrf2 signaling; polycystic ovary syndrome; reactive oxygen species; uterine decidualization
资金
- Swedish Medical Research Council [10380]
- Swedish Federal Fovernment under the LUA/ALF [ALFGBG-147791]
- Jane and Dan Olsson's Foundation
- Knut and Alice Wallenbergs Foundation
- Adlerbert Research Foundation
- National Natural Science Foundation of China [81774136]
- Project of Young Innovation Talents in Heilongjiang Provincial University [UNPYSCT-2015121]
- Project of Innovation Talents (Young Reserve Talents) in Harbin City [2015RAQYJ089]
- Scientific Research Foundation of the Heilongjiang Province for Returned Chinese Scholars
- Scientific Research Foundation for Postdoctoral Researcher of Heilong Jiang Province
- Project of Science Foundation by Heilongjiang University of Chinese Medicine
- Project of Excellent Innovation Talents by Heilongjiang University of Chinese Medicine
- Guangzhou Medical University High-level University Construction Talents Fund [B185006010046]
- Royal Society Dorothy Hodgkin Research Fellowship
- MRC [MR/R022690/1] Funding Source: UKRI
Women with polycystic ovary syndrome (PCOS) are at increased risk of miscarriage, which often accompanies the hyperandrogenism and insulin resistance seen in these patients. However, neither the combinatorial interaction between these two PCOS-related etiological factors nor the mechanisms of their actions in the uterus during pregnancy are well understood. We hypothesized that hyperandrogensim and insulin resistance exert a causative role in miscarriage by inducing defects in uterine function that are accompanied by mitochondrial-mediated oxidative stress. inflammation, and perturbed gene expression. Here, we tested this hypothesis by studying the metabolic, endocrine, and uterine abnormalities in pregnant rats after exposure to daily injection of 5adihydrotestosterone (DHT: 1.66 mg.kg body wt(-1).day(-1)) and/or insulin (6.0 IU/day) from gestational day 7.5 to 13.5. We showed that whereas DHT-exposed and insulin-exposed pregnant rats presented impaired insulin sensitivity, DHT + insulin-exposed pregnant rats exhibited hyperandrogenism and peripheral insulin resistance, which mirrors pregnant PCOS patients. Compared with controls, hyperandrogenism and insulin resistance in the dam were associated with alterations in uterine morphology and aberrant expression of genes responsible for decidualization (Prl8a2, Fxyd2, and Mt1g), placentation (Fcgr3 and Tpbpa). angiogenesis (Flt1, Angpt1. Angpt2, Ho1, Ccl2, Ccl5, Cxcl9, and Cxcl10) and insulin signaling (Akt, Gsk3, and Gluts). Moreover, we observed changes in uterine mitochondrial function and homeostasis (i.e., mitochondrial DNA copy number and the expression of genes responsible for mitochondrial fusion, fission. biogenesis, and mitophagy) and suppression of both oxidative and antioxidative defenses (i.e.. reactive oxygen species, Nrf2 signaling, and interactive networks of antioxidative stress responses) in response to the hyperandrogenism and insulin resistance. These findings demonstrate that hyperandrogenism and insulin resistance induce mitochondria-mediated damage and a resulting imbalance between oxidative and antioxidative stress responses in the gravid uterus.
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