Effectiveness of 2-methoxyestradiol in alleviating angiogenesis induced by intracranial venous hypertension

Abstract

OBJECT Intracranial dural arteriovenous fistulas (DAVFs) are complex intracranial vascular malformations that can lead to hemorrhage. The authors recently found that chronic local hypoperfusion seems to be the main cause of angiogenesis in the dura mater, which leads to the formation of DAVFs. As a natural derivative of estradiol, 2-methoxyestradiol (2-ME) has an antiangiogenic effect and can be used safely in patients with advanced carcinoid tumors. This study was conducted to examine the antiangiogenic effects of 2-ME on a rat DAVF model. METHODS Male Sprague-Dawley rats (n = 72) were used in the experiments. Intracranial venous hypertension was induced for modeling, and 2-ME was used in the early or late stage for treatment. The effects were examined by immunohistochemistry, Western blot analysis, and quantitative real-time polymerase chain reaction assays. RESULTS 2-Methoxyestradiol significantly reduced angiogenesis in the dura in early- and late-intervention treatment groups, as proven by the results of immunohistochemical staining, Western blotting, real-time polymerase chain reaction assays, and microvessel density counts. The antiangiogenic effect even lasted for up to 2 weeks after 2-ME cessation. CONCLUSIONS These data collectively suggest that 2-ME can reduce the angiogenic effect caused by venous hypertension in a rat DAVF model, mainly by suppressing the inhibitor of differentiation 1 (ID-1) and hypoxia-inducible factor 1α (HIF-1α) pathways.

Keywords: 2-ME = 2-methoxyestradiol; 2-methoxyestradiol; DAVF; DAVF = dural arteriovenous fistula; EJV = external jugular vein; GAPDH = glyceraldehyde 3-phosphate dehydrogenase; HIF-1α; HIF-1α = hypoxia-inducible factor 1α; ID-1; ID-1 = inhibitor of differentiation 1; MMP = matrix metalloproteinase; MVD = microvessel density; RT-PCR = real-time polymerase chain reaction; VEGF = vascular endothelial growth factor; angiogenesis; rat; vascular disorders.