Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development

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Item Type:	Article
Title:	Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development
Creators Name:	Abramsson, A., Kurup, S., Busse, M., Yamada, S., Lindblom, P., Schallmeiner, E., Stenzel, D., Sauvaget, D., Ledin, J., Ringvall, M., Landegren, U., Kjellén, L., Bondjers, G., Li, J.P., Lindahl, U., Spillmann, D., Betsholtz, C. and Gerhardt, H.
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.
Keywords:	PDGF-B, Angiogenesis, Heparan Sulfate, Pericyte, Vascular Development, Animals, Mice
Source:	Genes & Development
ISSN:	0890-9369
Publisher:	Cold Spring Harbor Laboratory Press
Volume:	21
Number:	3
Page Range:	316-331
Date:	1 February 2007
Official Publication:	https://doi.org/10.1101/gad.398207
PubMed:	View item in PubMed

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