基质金属蛋白酶抑制剂治疗脑动静脉畸形血管病态增生的作用机制和实验研究

Brain arteriovenous malformation (BAVM) is consisted by dynamic nidus due to abnormal vascular malformation with high risk of hemorrhage, and is a serious life-threatening cerebral disease in young adults. Considering the high risks and limitation of surgical removal, endovascular embolisation and radiotherapy for BAVM, it is necessary to explore the new angiogenesis inhibition therapy to prevent BAVM enlargement and rupture.Our previous researches suggest that matrix metalloproteinases (MMPs) played a very important role in the formation, development and rupture pathology of BAVM, so suppression of MMPs over-expression is expected to become a new way of BAVM inhibition treatment. Therefore, this study intends to use human BAVM vascular endothelial cells culturing, rat BAVM model, MMPs inhibitor doxycycline, multi photon-microscope, synchrotron radiation and other advanced imaging technique to: first, evaluate the inhibitory effect of doxycycline treatment for proliferation, migration, and tube formation ability of human BAVM vascular endothelial cells by in vitro experiment and vascular dysplasia of rat BAVM model by in vivo experiment.; second, explore the regulatory mechanisms of doxycycline treatment such as inhibition of various angiogenesis factors, like VEGF, BDGF, HIF-1α or TNF-β, and the introduction of tissue inhibitor of metalloproteinases (TIMPs) over expression. The results of this study will provide further evidence for the pathogenesis BAVM and also offer a novel therapeutic strategy for prevention of BAVM development.

脑动静脉畸形(BAVM)是脑内动静脉沟通形成的异常畸形血管团，存在破裂出血的高风险，是青壮年脑出血的主要病因。鉴于手术、介入和放射治疗在治疗BAVM过程中存在的风险性和局限性，故有必探索针对BAVM的血管形成抑制治疗新方法。我们前期研究提示基质金属蛋白酶(MMPs)在BAVM的发生发展和破裂出血的过程中起重要作用，通过抑制MMPs过表达有望成为控制BAVM发展的新途径。因此，本研究拟通过人BAVM血管内皮细胞，大鼠BAVM模型，MMPs抑制剂多西环素，同步辐射和双光子显微镜等先进影像技术，探索1)多西环素是否对人BAVM内皮细胞的增殖、迁移、成管以及大鼠BAVM模型血管病态增生有抑制作用；2)多西环素是否通过抑制血管生成因子和促进金属蛋白酶组织抑制因子(TIMPs)过表达，发挥抑制血管病态增生的作用。本研究结果将为BAVM的发病机制增加理论依据和防治BAVM的进展提供新策略。

脑动静脉畸形(BAVM)是脑内动静脉沟通形成的异常畸形血管团，存在破裂出血的高风险，是青壮年脑出血的主要病因。鉴于手术、介入和放射治疗在治疗BAVM过程中存在的风险性和局限性，故有必探索针对BAVM的血管形成抑制治疗新方法。本研究拟通过人BAVM血管内皮细胞，大鼠BAVM模型，MMPs抑制剂多西环素，7T磁共振等，证明了：1) MMP-3基因对人脑血管内皮细胞的增殖、迁移、成管有促进作用；2)体外多西环素对人脑血管内皮细胞的增殖、迁移、成管有抑制作，发挥抑制血管病态增生的作用；3) MMP-3在颅内静脉高压大鼠脑内高表达；4)多西环素能够在大鼠体内显著抑制MMP-3高表达，减少微血管密度。本项目的研究提示MMP-3在BAVM的发生发展和破裂出血的过程中起重要作用，通过抑制MMP-3过表达可成为控制BAVM发展的新途径，为BAVM的发病机制增加理论依据和防治BAVM的进展提供新策略。