ArticleThe Journal of biological chemistry2012
Endothelial heparan sulfate 6-O-sulfation levels regulate angiogenic responses of endothelial cells to fibroblast growth factor 2 and vascular endothelial growth factor.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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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.
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Who cites it
42 citing papers in PubMed, 82 citations in OpenAlex.
- Regulated HSPG Signaling Directs Epicardial Behavior to Support Cardiac Formation.Circulation research · 2026Article
- Article
- Multimodal Profiling Reveals Distinct Endothelial Activation Pathways Regulated by Flow and Heparan Sulfate.Cellular and molecular bioengineering · 2026Article
- Article
- Unraveling the Potential of Small Molecule Heparin Glycomimetics in Neuroregenerative Therapeutics.Journal of the American Chemical Society · 2025Article
- Heparan sulfate as a central modulator of growth factor dynamics in tissue regeneration.APL bioengineering · 2025Article
- Antiangiogenic Activity of 6-O-Desulfated Modified Heparin: Suppression of Choroidal Neovascularization.International journal of molecular sciences · 2025Article
- The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis.Cellular and molecular life sciences : CMLS · 2024Article
- Trauma promotes heparan sulfate modifications and cleavage that disrupt homeostatic gene expression in microvascular endothelial cells.Frontiers in cell and developmental biology · 2024Article
- Article
- Reproducing extracellular matrix adverse remodelling of non-ST myocardial infarction in a large animal model.Nature communications · 2023Article
- HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease.International journal of molecular sciences · 2023Review
- Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function.Matrix biology plus · 2022Review
- Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice.Discover oncology · 2021Article
- Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression.Frontiers in oncology · 2021Review
- Heparan sulfate functions are altered in the osteoarthritic cartilage.Arthritis research & therapy · 2020Article
- Function of fibroblast growth factor 2 in gastric cancer occurrence and prognosis.Molecular medicine reports · 2020Article
- Loss of endothelial sulfatase-1 after experimental sepsis attenuates subsequent pulmonary inflammatory responses.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- Targeting the Extracellular Matrix Promotes Healing Following Myocardial Infarction.Circulation research · 2019Article
- Downstream Products are Potent Inhibitors of the Heparan Sulfate 2-O-Sulfotransferase.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor 165 (VEGF(165)) are potent pro-angiogenic growth factors that play a pivotal role in tumor angiogenesis. The activity of these growth factors is regulated by heparan sulfate (HS), which is essential for the formation of FGF2/FGF receptor (FGFR) and VEGF(165)/VEGF receptor signaling complexes. However, the structural characteristics of HS that determine activation or inhibition of such complexes are only partially defined. Here we show that ovarian tumor endothelium displays high levels of HS sequences that harbor glucosamine 6-O-sulfates when compared with normal ovarian vasculature where these sequences are also detected in perivascular area. Reduced HS 6-O-sulfotransferase 1 (HS6ST-1) or 6-O-sulfotransferase 2 (HS6ST-2) expression in endothelial cells impacts upon the prevalence of HS 6-O-sulfate moieties in HS sequences, which consist of repeating short, highly sulfated S domains interspersed by transitional N-acetylated/N-sulfated domains. 1-40% reduction in 6-O-sulfates significantly compromises FGF2- and VEGF(165)-induced endothelial cell sprouting and tube formation in vitro and FGF2-dependent angiogenesis in vivo. Moreover, HS on wild-type neighboring endothelial or smooth muscle cells fails to restore endothelial cell sprouting and tube formation. The affinity of FGF2 for HS with reduced 6-O-sulfation is preserved, although FGFR1 activation is inhibited correlating with reduced receptor internalization. These data show that 6-O-sulfate moieties in endothelial HS are of major importance in regulating FGF2- and VEGF(165)-dependent endothelial cell functions in vitro and in vivo and highlight HS6ST-1 and HS6ST-2 as potential targets of novel antiangiogenic agents.
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Registered trials
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.