Underlying mechanisms for the pro-angiogenic phenotype of AVMs

结合了生物力学方法和两个独特的动物模型系统，模拟了两个不同的 对于脑动静脉畸形(AVM)的某些方面，我们的新提案将侧重于确定 在细胞和结构水平上抑制基质金属蛋白酶的后果。我们将演示异常情况 动静脉畸形中基质金属蛋白酶(MMPs)的水平和由此导致的血管不稳定是由于 两种机制联合高血流诱导炎性和炎性细胞基质金属蛋白酶的表达 血管细胞和AVM血管细胞的固有特性使其异常高表达MMPs。什么时候 起源于这两种潜在机制的MMPs被药物或药物抑制 从基因上取消，它会在结构和细胞水平上恢复血管的稳定性。特定的 目的1：高血流量诱导的基质金属蛋白酶和炎症对血液结构完整性的作用 船只。我们假设高血流率会增加血管壁中的基质金属蛋白酶水平，并导致 血管不稳定。高血流量诱导的基质金属蛋白酶表达引起的血管结构不稳定 /激活可被抑制MMPs逆转。特异靶2：基质金属蛋白酶-9异常表达的作用 动静脉畸形血管细胞对维持促血管生成表型的作用。我们假设 动静脉畸形血管细胞表达异常高水平的基质金属蛋白酶-9是其固有特性， 异常高水平的基质金属蛋白酶-9会导致血管不稳定。脑内和脑下植入的动静脉畸形组织 肾被膜保留固有的促血管生成表型，高水平的基质金属蛋白酶-9和基质金属蛋白酶-9相关 对照组织(颞浅动脉和正常脑)中其他血管生成因子的变化 皮质样本)保持血管生成静止的表型。基质金属蛋白酶的抑制改变了植入的动静脉畸形 组织从促血管生成表型向静止和稳定表型转变 其他血管生成因子的可用性，如血管内皮生长因子。意义：这个项目将阐明两个潜在的 动静脉畸形中基质金属蛋白酶-9异常表达的机制此外，我们还将证明，基质金属蛋白酶 抑制可以改变AVM组织的血管生成表型，恢复血管结构的稳定性。 这项研究的发现将为开发基质金属蛋白酶抑制疗法以恢复血管提供基础 患者动静脉动静脉畸形的稳定性，并防止未来的出血。

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.