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. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 225 Continuation Format Page Principal Investigator/Program Director (Last. First, Middle): PI: Hashimoto, T / Director: Young, WL. Introduction We would like to thank the study section for many positive and constructive comments that enabled us to refine and focus our project. The original proposal for Project 2 submitted in May 2007 received a score of 1.9. The committee pointed out that this proposal is """"""""a good project with interesting ideas and using innovative molecular tools"""""""" and that """"""""the pilot data is relatively strong,"""""""" The committee also noted """"""""the interactions with other projects and cores are very good"""""""". Four main suggestions for improvement from the committee included (1) the need to more carefully define hemodynamic conditions in the flow augmentation models, (2) the need to be careful with difficult controls in the implantation models, (3) the need to carefully define how inflammatory baselines might alter outcomes in the SCID mice, and (4) the need to pay some attention to consequences of long term MMP suppression. In addition, the committee noted some question regarding the appropriateness of the proposed models. We will address these five points raised by the committee, followed by specific critiques from each reviewer. As shown in this paragraph, major changes in the text are denoted by a double line in the right margin of the text and identified by a bracketed marker (e.g.,
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