title: Vascular endothelial growth factor (VEGF) regulation by hypoxia inducible factor-1 alpha (HIF1A) starts and peaks during endometrial breakdown, not repair, in a mouse menstrual-like model.
abstract: OBJECTIVE
  How is vascular endothelial growth factor (VEGF) expression regulated by hypoxia inducible factor 1 alpha (HIF1A) during menstruation?
  
  
  CONCLUSIONS
  After progesterone (P4) withdrawal, HIF1A was activated and it directly up-regulated VEGF mRNA expression and this regulation was the highest during endometrium breakdown in the mouse menstrual-like model.
  
  
  BACKGROUND
  VEGF, an important angiogenic factor, is known to be essential for endometrial repair, particularly in angiogenesis and re-epithelialization. However, its upstream regulation has not been fully clarified. HIF1 is the first transcription factor response to hypoxia and is closely associated with angiogenesis; it is also an upstream regulator of VEGF mRNA.
  
  
  METHODS
  We investigated the changes in the expression of HIF1A and VEGF after P4 withdrawal and after HIF1A inhibition. The total number of mice used was 62. The treatment duration in the mouse menstrual-like model was 8 days.
  
  
  METHODS
  The mouse menstrual-like model and mouse and human decidual endometrial stromal cells were established to mimic menstruation. Protein and mRNA expressions of HIF1A and VEGF were investigated by immunohistochemistry, Western blot and quantitative PCR. The direct interaction between HIF1A and the Vegf promoter was also investigated by chromatin immunoprecipitation. HIF1A inhibition in vivo and in vitro was achieved by administration of an HIF1A inhibitor and by siRNA knockdown, respectively.
  
  
  RESULTS
  HIF1A was translocated to the nucleus from 8 to 16 h after P4 withdrawal, while VEGF mRNA expression was the highest at 12 h. HIF1A directly bound to Vegf promoter during endometrial breakdown, which peaked at 12 h. HIF1A inhibition suppressed VEGF mRNA and protein expression in the mouse menstrual-like model and decidualized stromal cells. Inhibition of HIF1A also suppressed endometrial breakdown.
  
  
  CONCLUSIONS
  Although HIF1A regulation of VEGF mRNA was confirmed in the mouse menstrual-like model and decidual endometrium stromal cells, the functional regulation of VEGF protein was not further determined.
  
  
  CONCLUSIONS
  Here, we report that the functional regulation of VEGF was complicate in menstruation. We also report that HIF1A plays a key role in endometrial breakdown.
  
  
  BACKGROUND
  The National Nature Science Foundation of China (No. 30901608), the National Basic Research Program of China (2010CB530403) and the National Science and Technology Support Program (No. 2012BAI32B05). The authors have no conflicts of interest to disclose.
  
  
  BACKGROUND
  This study is not a clinical trial.
authors.affiliation: Reproductive Physiology Laboratory, National Research Institute for Family Planning, No.12 Dahuisi Road, Haidian District, Beijing 100081, People's Republic of China.
authors.forename: Xihua
authors.initials: X
authors.lastname: Chen
authors.affiliation: Reproductive Physiology Laboratory, National Research Institute for Family Planning, No.12 Dahuisi Road, Haidian District, Beijing 100081, People's Republic of China Graduate School of Peking Union Medical College, Beijing 100730, People's Republic of China.
authors.forename: Jianbing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Reproductive Physiology Laboratory, National Research Institute for Family Planning, No.12 Dahuisi Road, Haidian District, Beijing 100081, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Basic Medical College, Hebei University of Chinese Medicine, Shijiazhuang 050091, People's Republic of China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pre-clinical Sciences, Guangxi Medical University, Nanning 530021, People's Republic of China.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Reproductive Medicine, Jinan Central Hospital Affiliated to Shandong University, Jinan 250031, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Reproductive Physiology Laboratory, National Research Institute for Family Planning, No.12 Dahuisi Road, Haidian District, Beijing 100081, People's Republic of China Graduate School of Peking Union Medical College, Beijing 100730, People's Republic of China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Reproductive Physiology Laboratory, National Research Institute for Family Planning, No.12 Dahuisi Road, Haidian District, Beijing 100081, People's Republic of China.
authors.forename: Shucheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Reproductive Physiology Laboratory, National Research Institute for Family Planning, No.12 Dahuisi Road, Haidian District, Beijing 100081, People's Republic of China xiangboxuhappy@126.com.
authors.forename: Xiangbo
authors.initials: X
authors.lastname: Xu
authors.affiliation: Reproductive Physiology Laboratory, National Research Institute for Family Planning, No.12 Dahuisi Road, Haidian District, Beijing 100081, People's Republic of China.
authors.forename: Jiedong
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D003656:Decidua / Q000378:metabolism*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008598:Menstruation / Q000378:metabolism*; D051379:Mice; D023421:Models, Animal; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: endometrium breakdown; hypoxia inducible factor 1 alpha; menstruation; mouse menstrual-like model; vascular endothelial growth factor