Browsing by Author "Davari, Paniz"

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    Characterizing the role of Rasa1 in vascular development in zebrafish
    (2015-04-20) Davari, Paniz; Childs, Sarah J
    Vascular malformation syndromes arise during embryonic development and can have devastating effects on the quality of life of patients. Capillary malformations present with the overgrowth and permanent dilation of the capillaries under the skin but are often accompanied by fast-flow arteriovenous malformations in other internal organs. Recently, mutations in the GTPase activating protein RASA1 were found to be one cause of capillary malformation- arteriovenous malformation (CM-AVM). I set out to model CM-AVM in the zebrafish and found that loss of rasa1 leads to a large arteriovenous malformation that connects the artery and vein without intervening capillaries. In wild-type zebrafish embryos, a distinct aorta and a caudal vein plexus are visible in the tail region. However, in rasa1a morphants, there is an enlarged single vessel instead of a plexus, and this vessel fails to develop sprouts. Arteriovenous shunts develop commonly in this region. I next examined the mechanism by which rasa1 functions. I found that rasa1a genetically interacts with rras but not farnesyl- modified ras (rat sarcoma) genes. rasa1a also functions in parallel pathway to rras2. Finally, I showed misregulation of vegfc (vascular growth factor c) and vegfr3 (vascular growth factor receptor 3) in rasa1a morphants, suggesting rasa1a loss leads to misregulation of venous signaling pathways.