title: Regulation of Vegf signaling by natural and synthetic ligands.
abstract: The mechanisms that allow cells to bypass anti-vascular endothelial growth factor A (VEGFA) therapy remain poorly understood. Here we use zebrafish to investigate this question and first show thatvegfaamutants display a severe vascular phenotype that can surprisingly be rescued to viability byvegfaamessenger RNA injections at the 1-cell stage. Usingvegfaamutants as an in vivo test tube, we found that zebrafish Vegfbb, Vegfd, and Pgfb can also rescue these animals to viability. Taking advantage of a newvegfr1tyrosine kinase-deficient mutant, we determined that Pgfb rescuesvegfaamutants via Vegfr1. Altogether, these data reveal potential resistance routes against current anti-VEGFA therapies. In order to circumvent this resistance, we engineered and validated new dominant negative Vegfa molecules that by trapping Vegf family members can block vascular development. Thus, our results show that Vegfbb, Vegfd, and Pgfb can sustain vascular development in the absence of VegfA, and our newly engineered Vegf molecules expand the toolbox for basic research and antiangiogenic therapy.
authors: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Andrea
authors: 0000-0001-5863-6448
authors: A
authors: Rossi
authors: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Sebastien
authors: S
authors: Gauvrit
authors: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Michele
authors: M
authors: Marass
authors: Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA; and.|China Zebrafish Resource Center, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
authors: Luyuan
authors: L
authors: Pan
authors: Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA; and.
authors: Cecilia B
authors: CB
authors: Moens
authors: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Didier Y R
authors: DYR
authors: Stainier
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001158:Arteries / Q000254:growth & development / Q000473:pathology; D002454:Cell Differentiation; D005799:Genes, Dominant; D008024:Ligands; D009154:Mutation / Q000235:genetics; D018919:Neovascularization, Physiologic; D015202:Protein Engineering; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D008024:Ligands; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; D040281:Vascular Endothelial Growth Factor Receptor-1