Evidence map›Paper›PMID 27225479›Full record

ArticleCirculation research2016

Functional Importance of a Proteoglycan Coreceptor in Pathologic Lymphangiogenesis.

Scott C Johns, Xin Yin, Michael Jeltsch, Joseph R Bishop, Manuela Schuksz, Roland El Ghazal, Sarah A Wilcox-Adelman, Kari Alitalo, Mark M Fuster

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Article in Circulation research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.

0numbers the graph read from it
0cells of the map it votes in
23citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

23 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
  4. Regulation of VEGFR3 signaling in lymphatic endothelial cells.Frontiers in cell and developmental biology · 2025
    Review
  5. Review
  6. Article
  7. Article
  8. Review
  9. Article
  10. Article
  11. Review
  12. Review
  13. Article
  14. Review
  15. Review
  16. Review
  17. Review
  18. Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment.International journal of molecular sciences · 2020
    Review
  19. Article
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Scott C JohnsFrom 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.).
Xin YinFrom 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.).
Michael JeltschFrom 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.).
Joseph R BishopFrom 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.).
Manuela SchukszFrom 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.).
Roland El GhazalFrom 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.).
Sarah A Wilcox-AdelmanFrom 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.).
Kari AlitaloFrom 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.).
Mark M FusterFrom 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.

Funding

Siglec Modulation of Inflammation in Humans and MiceP01HL057345 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ESKO, JEFFREY D · 1997 to 2012
$24.1M
Training in Respiratory Biology: Innovate, Integrate, and TranslateT32HL098062 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI POWELL, FRANK L. · 2010 to 2014
$2.1M
Lymphatic Microenvironment: Altering Cell Traffic by Targeting GlycansR01HL107652 · NHLBI · VETERANS MEDICAL RESEARCH FDN/SAN DIEGO · PI FUSTER, MARK M · 2012 to 2015
$1.2M
Glycosaminoglycans and Cell Traffic in the Lymphatic MicroenvironmentI01BX000987 · VA · VA SAN DIEGO HEALTHCARE SYSTEM · PI FUSTER, MARK M · 2011 to 2012
–
NHLBI NIH HHS R01 HL107652
6 · The paper itself

Abstract

rationaleLymphatic 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.

objectiveTo explore the genetic basis and mechanisms, whereby heparan sulfate proteoglycans mediate pathological lymphatic remodeling. METHODS AND

resultsLymphatic 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.

conclusionsThese 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.

Indexed as

AnimalsCells, CulturedHumansLungLymphangiogenesisLymphatic VesselsMiceProteoglycansVascular Endothelial Growth Factor CVascular Endothelial Growth Factor Receptor-3ProteoglycansVascular Endothelial Growth Factor CVascular Endothelial Growth Factor Receptor-3apoptosislymphangiogenesisphosphorylationproteoglycansVEGF receptor

Identifiers

PMID27225479
PMCPMC4938725

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.