• Xiang Zou, Zehan Wu, Jun Huang, Peixi Liu, Xuanfeng Qin, Liang Chen, Wei Zhu, Yao Zhao, Peiliang Li, Jianping Song, Guo-Yuan Yang, and Ying Mao.
• Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
• Neurosurgery. 2018 Dec 1; 83 (6): 1317-1327.

BackgroundThe molecular mechanism of brain arteriovenous malformation (BAVM) is largely unknown. Intracranial venous hypertension (VH) may enhance focal angiogenesis and promote BAVM development and progression. A rat VH model effectively simulates the hemodynamic microenvironment of this disease.ObjectiveTo explore the effect of doxycycline in VH-related angiogenesis, as well as the role of matrix metalloproteinase-3 (MMP-3) and other molecular factors.MethodsA rat VH model was generated by common carotid artery and distal external jugular vein anastomosis. Microvessel density (MVD) in the perisinus area and expression of MMP-3/2/9, VEGF, TIMP-1, TGF-β, and HIF-1α were examined, with and without daily doxycycline treatment for 4 wk. The effects of doxycycline were verified in Vitro using human brain microvascular endothelial cells (HBMECs). MMP-3 overexpression or knockdown in HBMECs was used to confirm the role of MMP-3 in cell functions.ResultsMVD in the perisinus cortex was greatly increased after VH. Doxycycline decreased MVD, suppressed MMP-3 overexpression, and reduced VEGF, TGF-β, and TIMP-1 levels compared with the controls (P < .05). In Vitro, doxycycline decreased HBMEC migration, tube formation, and the mRNA, protein, and enzymatic activity levels of MMP-3. MMP-3 overexpression in HBMECs promoted migration, while knockdown of MMP-3 significantly attenuated proliferation, migration, and tube formation (P < .05).ConclusionOur findings indicate that MMP-3 plays an important role in VH-related angiogenesis and the promotion of vascular remodeling. Suppression of MMP-3 overexpression by doxycycline may provide a potential strategy for inhibiting BAVM development.

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