title: Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development.
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 beta (PDGFRbeta) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Matrix Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Abramsson
authors.forename: Sindhulakshmi
authors.initials: S
authors.lastname: Kurup
authors.forename: Marta
authors.initials: M
authors.lastname: Busse
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yamada
authors.forename: Per
authors.initials: P
authors.lastname: Lindblom
authors.forename: Edith
authors.initials: E
authors.lastname: Schallmeiner
authors.forename: Denise
authors.initials: D
authors.lastname: Stenzel
authors.forename: Dominique
authors.initials: D
authors.lastname: Sauvaget
authors.forename: Johan
authors.initials: J
authors.lastname: Ledin
authors.forename: Maria
authors.initials: M
authors.lastname: Ringvall
authors.forename: Ulf
authors.initials: U
authors.lastname: Landegren
authors.forename: Lena
authors.initials: L
authors.lastname: Kjellén
authors.forename: Göran
authors.initials: G
authors.lastname: Bondjers
authors.forename: Jin-ping
authors.initials: JP
authors.lastname: Li
authors.forename: Ulf
authors.initials: U
authors.lastname: Lindahl
authors.forename: Dorothe
authors.initials: D
authors.lastname: Spillmann
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
mesh_terms: D000818:Animals; D000077214:Becaplermin; D001808:Blood Vessels / Q000196:embryology*; D002465:Cell Movement; D019281:Dimerization; D004730:Endothelium, Vascular / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D020286:Pericytes / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis; D012249:Rhombencephalon / Q000196:embryology / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics
chemical_list: D000077214:Becaplermin; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D013431:Sulfates; D015238:Sulfotransferases; C021350:heparitin sulfotransferase