Brain arterial vascular malformations arise through a disruption in normal vascular homeostasis and excessive angiogenesis. Because normal angiogenesis requires that expression of a number of genes be temporally and spatially coordinated, we are investigating how the Homeobox (Hox) master transcription factor family of genes coordinates the expression of angiogenic or quiescent phenotypes in endothelial cells. We have identified Hox genes, which promote angiogenesis and those which attenuate angiogenesis and consequently favor maintenance of a quiescent differentiated state. Furthermore, the Hox genes impact the endothelial cell phenotype by coordinately modulating expression of extracellular matrix (ECM) components, their integdn receptors, as well as ECM degrading proteinases and their inhibitors. We hypothesize that an imbalance in pro-angiogenic Hox genes and angiostatic Hox genes contribute to the development of BAVMs and that restoring this balance can correct the aberrant vascular morphology and excessive angiogenesis associated with this disease. We will establish the patterns of expression of three Hox genes: Hox D3, Hox D10 and Hox A5 in normal and BAVM tissue. Secondly we will attempt to block cerebral angiogenesis in vivo by restoring expression or the angiostatic Hox D10 gene or attenuating expression of the pro-angiogenic Hox D3 gene. We will also explore whether Hox A5, known to inhibit proliferation of epithelial cells, can also inhibit endothelial cell growth and consequently angiogenesis. We will also investigate whether the downstream targets of Hox A5 are also genes involved in remodeling of the extracellular matrix.
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