title: VEGFR3 Modulates Vascular Permeability by Controlling VEGF/VEGFR2 Signaling.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) is the main driver of angiogenesis and vascular permeability via VEGF receptor 2 (VEGFR2), whereas lymphangiogenesis signals are transduced by VEGFC/D via VEGFR3. VEGFR3 also regulates sprouting angiogenesis and blood vessel growth, but to what extent VEGFR3 signaling controls blood vessel permeability remains unknown.
  
  
  OBJECTIVE
  To investigate the role of VEGFR3 in the regulation of VEGF-induced vascular permeability.
  
  
  RESULTS
  Long-term globalVegfr3gene deletion in adult mice resulted in increased fibrinogen deposition in lungs and kidneys, indicating enhanced vascular leakage at the steady state. Short-term deletion ofVegfr3in blood vascular endothelial cells increased baseline leakage in various tissues, as well as in tumors, and exacerbated vascular permeability in response to VEGF, administered via intradermal adenoviral delivery or through systemic injection of recombinant protein.VEGFR3gene silencing upregulated VEGFR2 protein levels and phosphorylation in cultured endothelial cells. Consistent with elevated VEGFR2 activity, vascular endothelial cadherin showed reduced localization at endothelial cell-cell junctions in postnatal retinas afterVegfr3deletion, or afterVEGFR3silencing in cultured endothelial cells. Furthermore, concurrent deletion ofVegfr2prevented VEGF-induced excessive vascular leakage in mice lackingVegfr3.
  
  
  CONCLUSIONS
  VEGFR3 limits VEGFR2 expression and VEGF/VEGFR2 pathway activity in quiescent and angiogenic blood vascular endothelial cells, thereby preventing excessive vascular permeability.
authors.affiliation: From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D'A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.).
authors.forename: Krista
authors.initials: K
authors.lastname: Heinolainen
authors.affiliation: From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D'A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.).
authors.forename: Sinem
authors.initials: S
authors.lastname: Karaman
authors.affiliation: From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D'A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.).
authors.forename: Gabriela
authors.initials: G
authors.lastname: D'Amico
authors.affiliation: From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D'A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.).
authors.forename: Tuomas
authors.initials: T
authors.lastname: Tammela
authors.affiliation: From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D'A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.).
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.affiliation: From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D'A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.).
authors.forename: Lauri
authors.initials: L
authors.lastname: Eklund
authors.affiliation: From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D'A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.).
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D'A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.). kari.alitalo@helsinki.fi georgia.zarkada@yale.edu.
authors.forename: Georgia
authors.initials: G
authors.lastname: Zarkada
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005838:Genotype; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000098:blood supply*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D010641:Phenotype; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D000099152:Cadherin 5; C467484:VEGFA protein, human; C467480:vascular endothelial growth factor A, mouse; C581309:FLT4 protein, human; C000588866:KDR protein, human; C000592875:Kdr protein, mouse
keywords: VE-Cadherin; VEGF receptor regulation; blood vessels; vascular biology; vascular leakage