Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Neurosurgery. 2018 Dec 1;83(6):1317-1327. doi: 10.1093/neuros/nyx633.
The 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.
To explore the effect of doxycycline in VH-related angiogenesis, as well as the role of matrix metalloproteinase-3 (MMP-3) and other molecular factors.
A 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.
MVD 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).
Our 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.
脑动静脉畸形（BAVM）的分子机制在很大程度上尚不清楚。颅内静脉高压（VH）可能增强局部血管生成，并促进 BAVM 的发展和进展。大鼠 VH 模型有效地模拟了这种疾病的血液动力学微环境。
探讨强力霉素在 VH 相关血管生成中的作用，以及基质金属蛋白酶-3（MMP-3）和其他分子因素的作用。
通过颈总动脉和远端颈外静脉吻合术建立大鼠 VH 模型。检测窦周区微血管密度（MVD）以及 MMP-3/2/9、VEGF、TIMP-1、TGF-β和 HIF-1α的表达，同时给予强力霉素治疗 4 周。在体外使用人脑微血管内皮细胞（HBMECs）验证强力霉素的作用。在 HBMECs 中过表达或敲低 MMP-3，以确认 MMP-3 在细胞功能中的作用。
VH 后窦周皮质 MVD 显著增加。与对照组相比，强力霉素降低了 MVD，抑制了 MMP-3 的过表达，并降低了 VEGF、TGF-β和 TIMP-1 的水平（P <.05）。在体外，强力霉素降低了 HBMEC 的迁移、管形成以及 MMP-3 的 mRNA、蛋白和酶活性水平。HBMECs 中 MMP-3 的过表达促进了迁移，而 MMP-3 的敲低则显著减弱了增殖、迁移和管形成（P <.05）。
我们的研究结果表明，MMP-3 在 VH 相关血管生成和血管重塑促进中发挥重要作用。强力霉素抑制 MMP-3 的过表达可能为抑制 BAVM 发展提供一种潜在策略。
