The Role of Matrix Metalloproteinase-3 in the Doxycycline Attenuation of Intracranial Venous Hypertension-Induced Angiogenesis
The Role of Matrix Metalloproteinase-3 in the Doxycycline Attenuation of Intracranial Venous Hypertension-Induced Angiogenesis
复制标题
基质金属蛋白酶-3 在强力霉素减弱颅内静脉高压诱导的血管生成中的作用
DOI：
10.1093/neuros/nyx633
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发表时间：
2018
期刊：
影响因子：
4.8
通讯作者：
Mao Ying
中科院分区：
文献类型：
--
作者：
Zou Xiang;Wu Zehan;Huang Jun;Liu Peixi;Qin Xuanfeng;Chen Liang;Zhu Wei;Zhao Yao;Li Peiliang;Song Jianping;Yang Guo Yuan;Mao Ying
背景
脑动静脉畸形（BAVM）的分子机制在很大程度上是未知的。颅内静脉高压（VH）可增强局灶性血管生成，促进BAVM的发生和进展。大鼠VH模型有效地模拟了这种疾病的血液动力学微环境。
目的
探讨强力霉素在血管增生相关血管生成中的作用，以及基质金属蛋白酶-3（MMP-3）等分子因子的作用。
方法
采用颈总动脉与颈外静脉远端吻合的方法建立大鼠VH模型。观察用药前后窦周区微血管密度（MVD）及MMP-3/2/9、VEGF、TIMP-1、TGF-β和HIF-1α的表达。用人脑微血管内皮细胞（HBMECs）体外验证了强力霉素的作用。MMP-3在HBMEC中的过表达或敲低用于证实MMP-3在细胞功能中的作用。
结果
Vh后，皮质周围区MVD明显增加。与对照组相比，强力霉素降低了MVD，抑制了MMP-3的过度表达，并降低了VEGF、TGF-β和TIMP-1的水平（P <0.05）。在体外，强力霉素降低HBMEC迁移，管形成，和MMP-3的mRNA，蛋白质和酶活性水平。MMP-3过表达促进HBMEC的迁移，而MMP-3敲低显著减弱增殖、迁移和管形成（P <0.05）。
结论
我们的研究结果表明，MMP-3在VH相关的血管生成和促进血管重塑中起着重要作用。多西环素抑制MMP-3的过度表达可能为抑制BAVM的发展提供了一种潜在的策略。
BACKGROUND
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.
OBJECTIVE
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.
METHODS
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.
RESULTS
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).
CONCLUSION
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.