Regulation of Artery-vein Identity in Arteriovenous Malformations associated with Hereditary Hemorrhagic Telangiectasia

Tulane University Of Louisiana, New Orleans LA

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Abstract

7. Project Summary/Abstract Tulane University Crist, Angela Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder that affects 1 in 5,000 individuals. Patients with HHT commonly exhibit misconnections between arteries and veins, called arteriovenous malformations (AVMs), which can rupture and lead to stroke or death. Unfortunately, the molecular mechanisms of AVM formation in HHT are poorly understood therefore no therapy has been developed. Our OBJECTIVE is to identify the molecular mechanism of AVM formation using a novel Smad4 inducible, endothelial cell specific knockout (Smad4-iECKO) mouse model. Our preliminary experiments in the murine retina revealed that loss of Smad4 caused 82% of our mice to develop AVMs. Furthermore, these mice exhibited loss of artery-vein (AV) identity, which we anticipate drives AVM formation. We HYPOTHESIZE that loss of Smad4 leads to AVM formation by directly altering AV identity. Using ChIP-seq, we have confirmed that Smad4 binds to many AV specific genes in a venous EC population. We propose to expand this study to include Smad4 binding sites in an arterial EC population. Using this information, we will identify evolutionarily conserved Smad4 binding regions in both EC populations and determine the biologically relevant sites that control AV gene expression. Furthermore, we will provide a comprehensive characterization of AV gene expression in Smad4 mutants and determine if these changes occur before or after AVM formation. This will allow us to assess if changes in AV identity are a cause or effect of AVM development. Overall, we will provide much needed insight into the role of AV identity in HHT pathogenesis. Furthermore, our studies will undoubtedly provide a better understanding of the TGF-Beta family's role in the endothelium by generating a comprehensive list of Smad4 binding sites in endothelial cells. This knowledge will allow researchers to link the TGF-Beta pathway to its respective target genes and will be relevant to other cardiovascular diseases such as coronary artery disease, endocarditis, and cardiomyopathy. !