2-Methoxyestradiol Inhibits Intracerebral Hemorrhage-Induced Angiogenesis In Rats

AIM: Angiogenesis occurs after intracerebral hemorrhage (ICH). Hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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 alpha. In the present study, we investigated the effect of 2ME2 in a rat model of ICH-induced angiogenesis.MATERIAL and 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-1a 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 alpha-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 alpha protein levels increased, while no change was observed in HIF-1 alpha mRNA expression after ICH. 2ME2 decreased the PCNA-labeled nuclei in cerebral ECs and down-regulated the expression of HIF-1 alpha protein as well, while it had little effect on the mRNA expression of HIF-1 alpha.CONCLUSION: HIF-1 alpha inhibitor, 2ME2, inhibited post-ICH angiogenesis by suppressing HIF-1 alpha expression, thus exerting detrimental effects in ICH.