title: The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching.
abstract: Blood vessel formation requires the integrated regulation of endothelial cell proliferation and branching morphogenesis, but how this coordinated regulation is achieved is not well understood. Flt-1 (vascular endothelial growth factor [VEGF] receptor 1) is a high affinity VEGF-A receptor whose loss leads to vessel overgrowth and dysmorphogenesis. We examined the ability of Flt-1 isoform transgenes to rescue the vascular development of embryonic stem cell-derived flt-1-/- mutant vessels. Endothelial proliferation was equivalently rescued by both soluble (sFlt-1) and membrane-tethered (mFlt-1) isoforms, but only sFlt-1 rescued vessel branching. Flk-1 Tyr-1173 phosphorylation was increased in flt-1-/- mutant vessels and partially rescued by the Flt-1 isoform transgenes. sFlt-1-rescued vessels exhibited more heterogeneous levels of pFlk than did mFlt-1-rescued vessels, and reporter gene expression from the flt-1 locus was also heterogeneous in developing vessels. Our data support a model whereby sFlt-1 protein is more efficient than mFlt-1 at amplifying initial expression differences, and these amplified differences set up local discontinuities in VEGF-A ligand availability that are important for proper vessel branching.
authors.affiliation: Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Kappas
authors.forename: Gefei
authors.initials: G
authors.lastname: Zeng
authors.forename: John C
authors.initials: JC
authors.lastname: Chappell
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Kearney
authors.forename: Surovi
authors.initials: S
authors.lastname: Hazarika
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Kallianos
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Brian H
authors.initials: BH
authors.lastname: Annex
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bautch
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000473:pathology*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D020033:Protein Isoforms; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D019076:Transgenes; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2