The Inhibitory Iffect Of 2-Methoxyestradiol On Angiogenesis In Dural Arteriovenous Fistula

Purpose:Dural arteriovenous fistula (DAVF) is a kind of persistent intracranial vascular disease, and its pathological basis is dural arteriovenous shunt which is related to angiogenesis. Our previous studies revealed that "sinus hypertension-brain tissue hypoperfusion-dura angiogenesis-DAVF formation" is the development process of the disease, suggesting that intervention of angiogenesis by medicine is expected to be a new strategy of DAVF-prevention.2-methoxyestradiol (2-ME) has been known as a potent anti-angiogenic agent. Clinical studies have indicated that 2-ME might play a role in the treatment of cancer through anti-angiogenesis, suggesting the inhibitory effect of 2-ME on the pathogenesis of DAVF. The study is therefore designed to detect the effects of 2-ME on angiogenesis in dura of the venous hypertension rat model. Methods:Firstly, we compared the pathological changes between people DAVF lesion sections and dura sections in rat intracranial venous hypertension model by immunohistochemical staining for angiogenetic factors such as VEGF, MMP-2/9, ID-land HIF-la. Then 2-ME was used to treat the animals at the early or late stage of intracranial venous hypertension model. The effects on angiogenesis were examined by immunohistochemistry, Elisa, western blot and RT-PCR methods. Results:The expressions of VEGF, MMP-2/9, ID-1 and HIF-la are in consistency between the two kinds of tissues, suggesting the similar pathology between people DAVF and rat intracranial venous hypertension model. Besides, treatment with 2-ME significantly reduced angiogenesis in the dura mater both in early- and late-treatment groups, which were evidenced by analyses for angigenetic factors with immunohistochemical staining, Elisa, Western blotting and RT-PCR and by microvessel density (MVD) counts. The anti-angiogenic effect could even last for 2 weeks after 2-ME cessation. Conclusions:Our data collectively demonstrate that 2-ME could reduce the angiogenesis in the dura mater caused by venous hypertension in rat models and that inhibition of angiogensis by 2-ME may serve as a new strategy in DAVF treatment.PartⅠThe modeling of venous hypertension rat and the uniformity between the model’s dura and human DAVF nidus in histopathologyPurpose:Dural arteriovenous fistula (DAVF) is an acquired disease; many patients have venous sinus hypertension before the onset of the disease. Through literature review, we believe that many of angiogenic factors, such as VEGF, MMP-2/9, ID-land HIF-1α, may be involved in the formation of DAVF. Since it’s still unclear wheather the expressions of these angiogenic factors were similar between intracranial venous hypertension rat model and human DAVF, we therefore compared the expressions of these angiogenic factors at first. Methods:We selected 18 human DAVF samples and 6 intracranial venous hypertension rats (12 weeks after modeling); VEGF, MMP-2/9, ID-land HIF-1α expressions were examined by immunohistochemistry. Results:The expressions of VEGF, MMP-2/9, ID-1 and HIF-1α were in consistency between the two kinds of tissues. Conclusions:Intracranial venous hypertension rat model is considered to represent part of the features of human DAVF in histopathology.Part Ⅱ2-Methoxyestradiol is effective in alleviating angiogenesis induced by intracranial venous hypertensionPurpose:Intracranial dura arteriovenous fistulas (DAVFs) are complex intracranial vascular malformations that can lead to hemorrhage. Recently, we found that chronic local hypoperfusion seemed to be the main cause of angiogenesis in the dura mater, leading to the formation of DAVFs. As a natural derivative of estradiol, 2-methoxyestradiol (2-ME) has an anti-angiogenic effect and can be safely used in patients with advanced carcinoid tumors. Therefore, this study was conducted to examine the anti-angiogenic effects of 2-ME on the rat DAVF model. Methods:78 male Sprague-Dawley rats were used in the experiment. Intracranial venous hypertension was made for modeling.2-ME was used in the early or late stage for treatment. The effects were examined by immunohistochemistry, Elisa, western blot and RT-PCR. Results: 2-ME significantly reduced angiogenesis in the dura mater in early-and late-treatment groups, which were proved by immunohistochemical staining, Elisa, Western blot, RT-PCR and microvessel density (MVD) counts. The anti-angiogenic effect can even last for 2 weeks after 2-ME cessation. Conclusions:Our data collectively suggest that 2-ME could reduce the angiogenic effect caused by venous hypertension in the rat DAVF model, mainly by suppressing the inhibitor of differentiation-1 (ID-1) and hypoxia-inducible factor 1-alpha (HIF-la) pathways.