title: Flt-1 (vascular endothelial growth factor receptor-1) is essential for the vascular endothelial growth factor-Notch feedback loop during angiogenesis.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF) signaling induces Notch signaling during angiogenesis. Flt-1/VEGF receptor-1 negatively modulates VEGF signaling. Therefore, we tested the hypothesis that disrupted Flt-1 regulation of VEGF signaling causes Notch pathway defects that contribute to dysmorphogenesis of Flt-1 mutant vessels.
  
  
  RESULTS
  Wild-type and flt-1(-/-) mouse embryonic stem cell-derived vessels were exposed to pharmacological and protein-based Notch inhibitors with and without added VEGF. Vessel morphology, endothelial cell proliferation, and Notch target gene expression levels were assessed. Similar pathway manipulations were performed in developing vessels of zebrafish embryos. Notch inhibition reduced flt-1(-/-) embryonic stem cell-derived vessel branching dysmorphogenesis and endothelial hyperproliferation, and rescue of flt-1(-/-) vessels was accompanied by a reduction in elevated Notch targets. Surprisingly, wild-type vessel morphogenesis and proliferation were unaffected by Notch suppression, Notch targets in wild-type endothelium were unchanged, and Notch suppression perturbed zebrafish intersegmental vessels but not caudal vein plexuses. In contrast, exogenous VEGF caused wild-type embryonic stem cell-derived vessel and zebrafish intersegmental vessel dysmorphogenesis that was rescued by Notch blockade.
  
  
  CONCLUSIONS
  Elevated Notch signaling downstream of perturbed VEGF signaling contributes to aberrant flt-1(-/-) blood vessel formation. Notch signaling may be dispensable for blood vessel formation when VEGF signaling is below a critical threshold.
authors.affiliation: Department of Biology, The University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Chappell
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Mouillesseaux
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bautch
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D049109:Cell Proliferation; D004151:Dipeptides / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D014680:Veins / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C583604:Vegfaa protein, zebrafish; D029961:Zebrafish Proteins; C467480:vascular endothelial growth factor A, mouse; C583603:FLT1 protein, zebrafish; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D053829:Amyloid Precursor Protein Secretases
keywords: Flt-1 protein, mouse; Notch receptors; angiogenesis; embryonic stem cells; vascular endothelial growth factor A; zebrafish