Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development.
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.
Abramsson
Alexandra
A
Department of Medical Biochemistry and Biophysics, Division of Matrix Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
Kurup
Sindhulakshmi
S
Busse
Marta
M
Yamada
Shuhei
S
Lindblom
Per
P
Schallmeiner
Edith
E
Stenzel
Denise
D
Sauvaget
Dominique
D
Ledin
Johan
J
Ringvall
Maria
M
Landegren
Ulf
U
Kjellén
Lena
L
Bondjers
Göran
G
Li
Jin-ping
JP
Lindahl
Ulf
U
Spillmann
Dorothe
D
Betsholtz
Christer
C
Gerhardt
Holger
H
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
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