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Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2007 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 21, no 3, 316-331 p.Article in journal (Refereed) Published
Abstract [en]

During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction of N-sulfation due to deficiency in N-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. Reduced N-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensively N- and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spaced N-sulfated domains to retain PDGF-BB and activate PDGF receptor β (PDGFRβ) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.

Place, publisher, year, edition, pages
2007. Vol. 21, no 3, 316-331 p.
Keyword [en]
PDGF-B, angiogenesis, heparan sulfate, pericyte, vascular development
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94740DOI: 10.1101/gad.398207ISI: 000244084700010PubMedID: 17289920OAI: oai:DiVA.org:uu-94740DiVA: diva2:168704
Available from: 2006-09-08 Created: 2006-09-08 Last updated: 2011-06-28Bibliographically approved
In thesis
1. Design of Oligosaccharide Libraries to Characterize Heparan Sulfate – Protein Interactions
Open this publication in new window or tab >>Design of Oligosaccharide Libraries to Characterize Heparan Sulfate – Protein Interactions
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfates (HSs) are a class of anionic carbohydrate chains found at cell surfaces and in the extracellular matrix where they interact with a number of proteins. HS is characterized by extreme structural heterogeneity, and has been implicated in a number of biological phenomenon like embryogenesis, morphogen gradient formation and signalling of growth factors such as FGF, PDGF etc. Despite the characteristic structural heterogeneity, evidence from compositional studies show that the HS structure is expressed in a tightly regulated manner, implying a functional significance, which is most likely in the modulation of cell behaviour through HS-protein interactions. The lack of molecular tools has, however, hampered the understanding of HS structures with functional significance. This work therefore aims at characterizing the structural requirements on HS involved in the interaction with the anti-HS phage display antibodies HS4C3, AO4B08 and HS4E4 and a selected growth factor PDGF-BB. The characterization was done with the help of tailored oligosaccharide libraries generated from sources bearing structural resemblance to HS.

The work has thus made available tools that preferentially recognize certain structural features on the HS chain and will aid in the further study of HS structure and its regulation. Evidence is also provided to support the notion that HS protein interactions can occur in multiple manners, utilizing any of the structural features on the HS chain.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 38 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 165
Biochemistry, heparan sulfate, oligosaccharide, phage display antibodies, Biokemi
urn:nbn:se:uu:diva-7095 (URN)91-554-6626-5 (ISBN)
Public defence
2006-09-28, C10:301, BMC, Husargatan,3, Uppsala, 09:15
Available from: 2006-09-08 Created: 2006-09-08Bibliographically approved

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Ringvall, MariaKjellén, LenaLi, Jin-PingLindahl, UlfSpillmann, Dorothe
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