title: Functional Importance of a Proteoglycan Coreceptor in Pathologic Lymphangiogenesis.
abstract: Lymphatic vessel growth is mediated by major prolymphangiogenic factors, such as vascular endothelial growth factor (VEGF-C) and VEGF-D, among other endothelial effectors. Heparan sulfate is a linear polysaccharide expressed on proteoglycan core proteins on cell membranes and matrix, playing roles in angiogenesis, although little is known about any function(s) in lymphatic remodeling in vivo.
  
  
  
  To explore the genetic basis and mechanisms, whereby heparan sulfate proteoglycans mediate pathological lymphatic remodeling.
  
  
  
  Lymphatic endothelial deficiency in the major heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1; involved in glycan-chain sulfation) was associated with reduced lymphangiogenesis in pathological models, including spontaneous neoplasia. Mouse mutants demonstrated tumor-associated lymphatic vessels with apoptotic nuclei. Mutant lymphatic endothelia demonstrated impaired mitogen (Erk) and survival (Akt) pathway signaling and reduced VEGF-C-mediated protection from starvation-induced apoptosis. Lymphatic endothelial-specific Ndst1 deficiency (in Ndst1(f/f)Prox1(+/CreERT2) mice) was sufficient to inhibit VEGF-C-dependent lymphangiogenesis. Lymphatic heparan sulfate deficiency reduced phosphorylation of the major lymphatic growth receptor VEGF receptor-3 in response to multiple VEGF-C species. Syndecan-4 was the dominantly expressed heparan sulfate proteoglycan in mouse lymphatic endothelia, and pathological lymphangiogenesis was impaired in Sdc4((-/-)) mice. On the lymphatic cell surface, VEGF-C induced robust association between syndecan-4 and VEGF receptor-3, which was sensitive to glycan disruption. Moreover, VEGF receptor-3 mitogen and survival signaling was reduced in the setting of Ndst1 or Sdc4 deficiency.
  
  
  
  These findings demonstrate the genetic importance of heparan sulfate and the major lymphatic proteoglycan syndecan-4 in pathological lymphatic remodeling. This may introduce novel future strategies to alter pathological lymphatic-vascular remodeling.
authors.affiliation: From the VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA (S.C.J., X.Y., R.E., M.M.F.); Division of Pulmonary and Critical Care, Department of Medicine, University of California San Diego, La Jolla (S.C.J., X.Y., R.E., M.M.F.); Marine Drug Research Institute, Huaihai Institute of Technology, Lianyungang, China (X.Y.); Translational Cancer Biology Research Program, Institute of Biomedicine (M.J.) and Helsinki University Central Hospital (K.A.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla (J.R.B., M.S.); Biomatrix Center, New York University (S.A.W.-A.); and Translational Cancer Biology Research Program, Wihuri Research Institute, Helsinki, Finland (K.A.).
authors.forename: Scott C
authors.initials: SC
authors.lastname: Johns
authors.affiliation: From the VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA (S.C.J., X.Y., R.E., M.M.F.); Division of Pulmonary and Critical Care, Department of Medicine, University of California San Diego, La Jolla (S.C.J., X.Y., R.E., M.M.F.); Marine Drug Research Institute, Huaihai Institute of Technology, Lianyungang, China (X.Y.); Translational Cancer Biology Research Program, Institute of Biomedicine (M.J.) and Helsinki University Central Hospital (K.A.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla (J.R.B., M.S.); Biomatrix Center, New York University (S.A.W.-A.); and Translational Cancer Biology Research Program, Wihuri Research Institute, Helsinki, Finland (K.A.).
authors.forename: Xin
authors.initials: X
authors.lastname: Yin
authors.affiliation: From the VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA (S.C.J., X.Y., R.E., M.M.F.); Division of Pulmonary and Critical Care, Department of Medicine, University of California San Diego, La Jolla (S.C.J., X.Y., R.E., M.M.F.); Marine Drug Research Institute, Huaihai Institute of Technology, Lianyungang, China (X.Y.); Translational Cancer Biology Research Program, Institute of Biomedicine (M.J.) and Helsinki University Central Hospital (K.A.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla (J.R.B., M.S.); Biomatrix Center, New York University (S.A.W.-A.); and Translational Cancer Biology Research Program, Wihuri Research Institute, Helsinki, Finland (K.A.).
authors.forename: Michael
authors.initials: M
authors.lastname: Jeltsch
authors.affiliation: From the VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA (S.C.J., X.Y., R.E., M.M.F.); Division of Pulmonary and Critical Care, Department of Medicine, University of California San Diego, La Jolla (S.C.J., X.Y., R.E., M.M.F.); Marine Drug Research Institute, Huaihai Institute of Technology, Lianyungang, China (X.Y.); Translational Cancer Biology Research Program, Institute of Biomedicine (M.J.) and Helsinki University Central Hospital (K.A.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla (J.R.B., M.S.); Biomatrix Center, New York University (S.A.W.-A.); and Translational Cancer Biology Research Program, Wihuri Research Institute, Helsinki, Finland (K.A.).
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bishop
authors.affiliation: From the VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA (S.C.J., X.Y., R.E., M.M.F.); Division of Pulmonary and Critical Care, Department of Medicine, University of California San Diego, La Jolla (S.C.J., X.Y., R.E., M.M.F.); Marine Drug Research Institute, Huaihai Institute of Technology, Lianyungang, China (X.Y.); Translational Cancer Biology Research Program, Institute of Biomedicine (M.J.) and Helsinki University Central Hospital (K.A.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla (J.R.B., M.S.); Biomatrix Center, New York University (S.A.W.-A.); and Translational Cancer Biology Research Program, Wihuri Research Institute, Helsinki, Finland (K.A.).
authors.forename: Manuela
authors.initials: M
authors.lastname: Schuksz
authors.affiliation: From the VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA (S.C.J., X.Y., R.E., M.M.F.); Division of Pulmonary and Critical Care, Department of Medicine, University of California San Diego, La Jolla (S.C.J., X.Y., R.E., M.M.F.); Marine Drug Research Institute, Huaihai Institute of Technology, Lianyungang, China (X.Y.); Translational Cancer Biology Research Program, Institute of Biomedicine (M.J.) and Helsinki University Central Hospital (K.A.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla (J.R.B., M.S.); Biomatrix Center, New York University (S.A.W.-A.); and Translational Cancer Biology Research Program, Wihuri Research Institute, Helsinki, Finland (K.A.).
authors.forename: Roland
authors.initials: R
authors.lastname: El Ghazal
authors.affiliation: From the VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA (S.C.J., X.Y., R.E., M.M.F.); Division of Pulmonary and Critical Care, Department of Medicine, University of California San Diego, La Jolla (S.C.J., X.Y., R.E., M.M.F.); Marine Drug Research Institute, Huaihai Institute of Technology, Lianyungang, China (X.Y.); Translational Cancer Biology Research Program, Institute of Biomedicine (M.J.) and Helsinki University Central Hospital (K.A.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla (J.R.B., M.S.); Biomatrix Center, New York University (S.A.W.-A.); and Translational Cancer Biology Research Program, Wihuri Research Institute, Helsinki, Finland (K.A.).
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Wilcox-Adelman
authors.affiliation: From the VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA (S.C.J., X.Y., R.E., M.M.F.); Division of Pulmonary and Critical Care, Department of Medicine, University of California San Diego, La Jolla (S.C.J., X.Y., R.E., M.M.F.); Marine Drug Research Institute, Huaihai Institute of Technology, Lianyungang, China (X.Y.); Translational Cancer Biology Research Program, Institute of Biomedicine (M.J.) and Helsinki University Central Hospital (K.A.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla (J.R.B., M.S.); Biomatrix Center, New York University (S.A.W.-A.); and Translational Cancer Biology Research Program, Wihuri Research Institute, Helsinki, Finland (K.A.).
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: From the VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA (S.C.J., X.Y., R.E., M.M.F.); Division of Pulmonary and Critical Care, Department of Medicine, University of California San Diego, La Jolla (S.C.J., X.Y., R.E., M.M.F.); Marine Drug Research Institute, Huaihai Institute of Technology, Lianyungang, China (X.Y.); Translational Cancer Biology Research Program, Institute of Biomedicine (M.J.) and Helsinki University Central Hospital (K.A.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla (J.R.B., M.S.); Biomatrix Center, New York University (S.A.W.-A.); and Translational Cancer Biology Research Program, Wihuri Research Institute, Helsinki, Finland (K.A.). mfuster@ucsd.edu.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Fuster
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000473:pathology* / Q000502:physiology*; D051379:Mice; D011509:Proteoglycans / Q000502:physiology*; D042582:Vascular Endothelial Growth Factor C / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000502:physiology*
chemical_list: D011509:Proteoglycans; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: VEGF receptor; apoptosis; lymphangiogenesis; phosphorylation; proteoglycans