Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development
- Alexandra Abramsson1,6,
- Sindhulakshmi Kurup2,6,
- Marta Busse3,
- Shuhei Yamada2,7,
- Per Lindblom3,8,
- Edith Schallmeiner4,
- Denise Stenzel3,
- Dominique Sauvaget3,
- Johan Ledin2,
- Maria Ringvall2,
- Ulf Landegren4,
- Lena Kjellén2,
- Göran Bondjers5,
- Jin-ping Li2,
- Ulf Lindahl2,
- Dorothe Spillmann2,
- Christer Betsholtz1, and
- Holger Gerhardt3,9
- 1 Department of Medical Biochemistry and Biophysics, Division of Matrix Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden;
- 2 Department of Medical Biochemistry and Microbiology, University of Uppsala, SE-751 23 Uppsala, Sweden;
- 3 Vascular Biology Laboratory, Cancer Research UK, Lincoln’s Inn Fields Laboratories, London WC 2A 3PX, United Kingdom;
- 4 Department of Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden;
- 5 Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, SE-413 45 Gothenburg, Sweden
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↵6 These authors contributed equally to this work.
Abstract
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.
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Footnotes
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↵7 Present addresses: Laboratory of Proteoglycan Signaling and Therapeutics, Hokkaido University, 5th floor Frontier Research Center for Post-Genomic Science and Technology, Nishi 11-choume, Kita 21-jo, Kita-ku, Sapporo 001-0021, Japan;
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↵8 Molecular Toxicology, Safety Assessment, AstraZeneca AB, SE-151 85 Södertälje, Sweden.
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↵9 Corresponding author.
↵9 E-MAIL holger.gerhardt{at}cancer.org.uk; FAX 44-207-269-3417.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.398207
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- Received June 21, 2006.
- Accepted December 5, 2006.
- Copyright © 2007, Cold Spring Harbor Laboratory Press