title: 2-Methoxyestradiol Inhibits Intracerebral Hemorrhage- Induced Angiogenesis in Rats.
abstract: OBJECTIVE
  Angiogenesis occurs after intracerebral hemorrhage (ICH). Hypoxia-inducible factor-1? (HIF-1?) is a critical regulator of angiogenesis. However, its role in the central nervous system remains controversial. 2-Methoxyestradiol (2ME2), a natural metabolite of estrogen, is known to inhibit HIF-1?. In the present study, we investigated the effect of 2ME2 in a rat model of ICH-induced angiogenesis.
  
  
  METHODS
  Sprague-Dawley male rats (n=50) were randomly divided into 5 groups: Sham operated group; ICH; ICH+2ME2; and ICH+Vehicle groups. ICH model was induced by stereotactic injection of collagenase type VII into the right globus pallidus. 2ME2 or vehicle (10% dimethyl sulfoxide) was administered intraperitoneally 10 min after ICH. Angiogenesis and expression of HIF-1? was evaluated by immunohistochemistry, quantitative real time-reverse transcription polymerase chain reaction and western blot, respectively.
  
  
  RESULTS
  Proliferating cell nuclear antigen (PCNA)-labeled nuclei were detected in cerebral endothelial cells (ECs) around the hematoma. The labeling peaked at 14 days post-ICH. HIF-1?-immunoreactive microvessels with dilated outline were detected in the perihematomal tissues. The vessels extended into the clot from the surrounding tissues from day 7 onwards. HIF-1? protein levels increased, while no change was observed in HIF-1? mRNA expression after ICH. 2ME2 decreased the PCNA-labeled nuclei in cerebral ECs and down-regulated the expression of HIF-1? protein as well, while it had little effect on the mRNA expression of HIF-1?.
  
  
  CONCLUSIONS
  HIF-1? inhibitor, 2ME2, inhibited post-ICH angiogenesis by suppressing HIF-1? expression, thus exerting detrimental effects in ICH.
authors.affiliation: China Three Gorges University, The First College of Clinical Medical Sciences, Department of Radiology, Yichang, Hubei, China.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Li
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Zhou
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Zhong
authors.forename: Tao
authors.initials: T
authors.lastname: Tang
authors.forename: Han-Jin
authors.initials: HJ
authors.lastname: Cui
authors.forename: Qi-Mei
authors.initials: QM
authors.lastname: Zhang
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Zhou
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D002543:Cerebral Hemorrhage / Q000473:pathology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004958:Estradiol; D000077584:2-Methoxyestradiol