R Dawn Fevurly, Sean Hasso, Alexander Fye, Steven J Fishman, Joanne Chan
Vascular Biology Program, Vascular Anomalies Center and Department of Surgery Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Journal of pediatric surgery 2012 JanLymphatic disorders are poorly understood with few animal models. We designed a novel assay to measure lymphatic development using transgenic zebrafish with fluorescently labeled endothelial cells. Two major branches of the vascular endothelial growth factor receptor (VEGFR) signaling pathway were examined: the MAPK and PI3K pathways. Direct visualization of lymphatic development was performed in control embryos or under chemical inhibition. Treatment involved a 6-hour pulse of inhibitor at 3 days postfertilization. Fish were analyzed for the presence of the thoracic duct (TD) at 4 days postfertilization (n > 100 specimens). Thoracic duct formation was prevented using selective inhibitors against kinases (MAPK, PI3K/TOR, or VEGFR). These kinases were important for TD formation because the lymphatic vessel failed to form in most of treated animals. Remarkably, MAPK pathway inhibition most robustly reduced lymphangiogenesis, demonstrated by a lack of lymphatic endothelial cells. We conclude that MAPK pathway function downstream of the VEGFRs is crucial at the early stages of TD development. This study provides a novel animal model and a potential target pathway for further investigation. We suggest further examination of MAPK pathway deregulation as a potential mechanism underlying lymphatic disease in humans. Copyright © 2012 Elsevier Inc. All rights reserved.
R Dawn Fevurly, Sean Hasso, Alexander Fye, Steven J Fishman, Joanne Chan. Novel zebrafish model reveals a critical role for MAPK in lymphangiogenesis. Journal of pediatric surgery. 2012 Jan;47(1):177-82
PMID: 22244413
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