Determining the pathophysiology of pediatric arteriovenous malformation

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The goal of this project is to understand the mechanisms by which arteriovenous malformation (AVM) forms and progresses. This will inform us about the fundamental process of vascular morphogenesis and, importantly, identify specific genes/pathways for which targeted therapies can be developed to improve the lives of patients affected by AVM and other vascular diseases. AVM is present at birth and undergoes significant progression over time. The lesion enlarges, bleeds, ulcerates, and causes pain and deformity. Vital structures can be threatened and congestive heart failure may occur. Currently, there is no cure for AVM and drug treatment does not exist. We recently found that most human AVMs contain somatic mutations in MAP2K1, and that this mutation is exclusive to the endothelial cell. We now aim to: (1) identify other somatic mutations in human AVMs, (2) determine how MAP2K1 mutations affect endothelial cell function, and (3) develop animal models of AVM to further study its pathophysiology as well as to test pharmacotherapy. We will perform molecular inversion probe, RNA, whole-exome, and whole genome sequencing on AVM tissues and isolated endothelial cells to find additional mutations in human AVMs. Mutant endothelial cells containing the MAP2K1 mutation will be studied to determine how the mutation affects signaling pathways, protein production, and the ability of the cells to interact with pericytes to form blood vessels. An animal model of AVM will be developed by inserting mutant MAP2K1 endothelial cells into immunodeficient mice, as we have successfully done with other types of vascular anomalies. FDA-approved inhibitors of MAP2K1 will be tested in vitro and in vivo to understand the pathophysiology of how the mutation affects cell behavior and to determine the efficacy of the drugs. These experiments will be high impact when we succeed in identifying the pathophysiology responsible for AVM formation and enlargement. For the first time we would be able to pursue a targeted approach for treating this lesion. For example, pathway specific topical, intralesional, and/or systemic pharmacologic agents could be developed to prevent AVM progression or recurrence. Discoveries into the pathophysiology of AVM also will help us to understand the mechanisms that underlie other pediatric vascular lesions, and will improve our ability to manipulate vascular growth in a broad range of diseases.