Underlying mechanisms for the pro-angiogenic phenotype of AVMs

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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.