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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.).
Published: July 2016
AI Article Synopsis
Article Abstract
Rationale: 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.
Objective: To explore the genetic basis and mechanisms, whereby heparan sulfate proteoglycans mediate pathological lymphatic remodeling.
Methods And Results: 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.
Conclusions: 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.
