Underlying mechanisms for the pro-angiogenic phenotype of AVMs

结合生物力学方法和两种独特的动物模型系统， 脑动静脉畸形（AVM）方面，我们的新建议将侧重于确定 MMP抑制在细胞和结构水平的后果。我们将证明， AVM中的基质金属蛋白酶（MMPs）水平和由此产生的血管不稳定性是由于 两种机制的结合 高血流速度诱导MMP表达， 血管细胞和AVM血管细胞的固有特性异常表达高水平的MMPs。当 这两种机制所产生的MMPs， 在遗传上被废除后，它会导致结构和细胞水平上血管稳定性的恢复。具体 目的1：高血流量诱导的MMPs和炎症对血液结构完整性的作用 船舶.我们假设高血流速度会增加血管壁MMP水平， 血管不稳定高血流量诱导MMP表达导致血管结构不稳定 /激活可以通过抑制MMPs来逆转。具体目标2：MMP-9异常表达的作用 从AVM血管细胞维持促血管生成表型。我们假设 AVM血管细胞表达异常高水平的MMP-9是其固有特性， 异常高水平的MMP-9导致血管不稳定。植入脑内和脑下的AVM组织 肾包膜保留了内在促血管生成表型高水平MMP-9和MMP-9相关 其他血管生成因子的变化，而对照组织（颞浅动脉和正常脑） 皮质样品）保持血管生成静止表型。MMP抑制改变植入的AVM 组织从促血管生成表型到静止和稳定表型， 其他血管生成因子如VEGF的可用性。意义：本项目将阐明两种潜在的 MMP-9在AVM中异常表达的机制。此外，我们将证明MMP 抑制可以改变AVM组织血管生成表型并恢复血管结构稳定性。 这项研究的结果将成为开发MMP抑制治疗以恢复血管的基础 稳定患者的AVM，并防止未来出血。

Combining a biomechanical approach and two unique animal model systems that mimic two different aspects of brain arteriovenous malformations (AVMs), our new proposal will focus on determining the consequences of MMP inhibition at the cellular and structural levels. We will demonstrate that the abnormal levels of matrix metalloproteinases (MMPs) in AVMs and resultant vascular instability are due to a combination of two mechanisms high blood flow rate induced MMP expression in inflammatory and vascular cells and AVM vascular cell's intrinsic property to abnormally express high levels of MMPs. When MMPs, which originated from these two underlying mechanisms, are inhibited pharmacologically or abolished genetically, it results in restoration of vascular stability at the structural and cellular levels. Specific Aim 1: Roles of high blood flow induced-MMPs and inflammation on structural integrity of blood vessels. We hypothesize that high blood flow rate will increase MMP levels in the vascular wall and cause vascular instability. Structural instability of blood vessels caused by high blood flow induced-MMP expression / activation can be reversed by inhibition MMPs. Specific Aim 2: Roles of abnormal expression of MMP-9 from AVM vascular cells on maintenance of pro-angiogenic phenotypes. We hypothesize that expression of abnormally high levels of MMP-9 by AVM vascular cells is their intrinsic property and that abnormally high levels of MMP-9 result in vascular instability. AVM tissues implanted in the brain and under the kidney capsule retain intrinsic pro-angiogenic phenotype high levels of MMP-9 and MMP-9 associated changes in other angiogenic factors while control tissues (superficial temporal artery and normal brain cortex samples) retain angiogenically quiescent phenotype. MMP inhibition changes the implanted AVM tissues from pro-angiogenic phenotype to quiescent and stable phenotype by decreasing the release and availability of other angiogenic factors such as VEGF. Significance: This project will elucidate two potential mechanisms for the abnormal expression of MMP-9 in AVMs. Furthermore, we will demonstrate that MMP inhibition can modify angiogenic phenotype of AVM tissues and restore structural stability of blood vessels. Findings from this study will be a basis for development of MMP inhibition treatment to restore vascular stability of AVMs in patients and prevent future hemorrhage.