Biochemical Society Transactions

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Cytokine–Proteoglycan Interactions: Biology and Structure

Heparan sulphate requirement in platelet-derived growth factor B-mediated pericyte recruitment

S. Kurup, A. Abramsson, J.P. Li, U. Lindahl, L. Kjellen, C. Betsholtz, H. Gerhardt, D. Spillmann


HS (heparan sulphate) plays a key role in angiogenesis, by interacting with growth factors required in the process. It has been proposed that HS controls the diffusion, and thus the availability, of platelet-derived growth factor B that is needed for pericyte recruitment around newly formed capillaries. The present paper summarizes our studies on the importance of HS structure in this regulatory process.

  • extracellular matrix
  • growth factor
  • heparan sulphate
  • pericyte recruitment
  • platelet-derived growth factor (PDGF)
  • retention motif


Heparan sulphates (HSs) are linear anionic polysaccharide chains that occur on cell surfaces and in the ECM (extracellular matrix). They are composed of repeating units of alternating glucosamine linked to a uronic acid. During HS biosynthesis, these disaccharide units undergo modification chiefly through replacement of glucosamine N-acetyl by N-sulphate groups, addition of O-sulphate groups, and C-5 epimerization of glucuronic acid to iduronic acid residues. By virtue of these differential modification possibilities, an HS disaccharide can exist in 48 different forms and is thus potentially the most information-dense structure known [1]. Due to the anionic nature of the HS chains, imparted by the sulphation, HSs at all cell surfaces or in the ECM readily interact with diverse ligands such as growth factors. PDGF (platelet-derived growth factor) is one such HS-binding growth factor.

PDGFs and their receptors

PDGF was originally purified as a proliferation factor from platelets. Four different family members (A, B, C and D) have been identified that form five different homo- and heterodimers of PDGF, namely AA, BB, AB, CC and DD. PDGFs are potent mitogens and chemoattractants that have critical roles in embryogenesis, angiogenesis and wound repair. Their biological effects are mediated through two structurally related tyrosine kinase receptors known as the α and β receptors. PDGF isoforms, being dimeric molecules, bind to two receptors and thus induce receptor dimerization. The α receptor binds both the A and B chains of PDGF, whereas the β receptor binds only the B chain with high affinity. Therefore PDGF-A induces αα receptor homodimers and PDGF-B all three dimeric combinations of α and β receptors. Each of the PDGF-A and -B chains appears as two variants, the long isoform and the short isoform. The two isoforms of the PDGF-A chain are due to translation of two different PDGF-A transcripts that are generated by alternative splicing. The B chain isoforms are, on the other hand, a result of post-translational proteolytic processing. Both the A and B long isoforms contain a highly basic amino acid sequence in their C-terminal extensions. These are referred to as retention motifs and are believed to mediate interaction between PDGF and the cell surface or the ECM [2]. These retention motifs appear to limit the action range of PDGF-B in vivo, as suggested from experiments with transplanted keratinocytes transfected with PDGF-B expression vectors [3]. The physiological importance of the retention motif was recently shown using mice that were lacking the PDGF-B retention motif due to targeted mutagenesis [4]. Such mice develop defective investment of pericytes in the microvessel wall and delayed formation of the renal glomerulus mesangium. An identical phenotype is seen in mice devoid of PDGFR β (PDGF receptor β), thus indicating the importance of PDGF-B/PDGFR β signalling in pericyte investment around vascular endothelial cells [5].

Pericyte recruitment and the importance of HS

Pericytes are cells embedded within the basement membrane surrounding capillary tubes. A variety of functions have been proposed for the pericyte, such as regulation of new capillary growth, regulation of capillary blood flow, or as precursors to vascular smooth-muscle cells etc. The absence of pericytes leads to a non-uniform capillary structure. It has been speculated that this effect may be due to abrogated control of pericytes over endothelial cell proliferation and differentiation. PDGF-B plays a critical role in the recruitment of the PDGFR β-expressing pericytes around newly formed capillaries, through a paracrine mode of action [6]. It has been shown that the amount of PDGF-B produced by the vascular endothelium is tightly regulated, expression occurring only at sites of active pericyte proliferation [7]. Pericyte coverage around the endothelium varies extensively between different tissues, presumably reflecting regulation of PDGF-B expression levels and availability. HSPGs (HS proteoglycans) have also been implicated in this process, as a means to store PDGF-B at cell surfaces and in the ECM. Interaction of PDGF-B with HSPGs could thus regulate the spatial distribution and availability of PDGF-B at sites of active pericyte proliferation such as the angiogenic sprouts. In this way, the procurement of the PDGFR β-expressing pericytes around the vascular endothelium may be controlled by the HSPGs. A functionally defective HSPG should therefore give rise to a phenotype that is defective in pericyte procurement. This aspect was investigated in mice lacking either one of the two enzymes involved in HS biosynthesis, NDST-1 (N-deacetylase/N-sulphotransferase-1) [8] and glucuronyl C-5-epimerase [9] (A. Abramsson, S. Kurup, S. Yamada, P. Lindblom, J. Ledin, M. Ringwall, L. Kjellén, G. Bondjers, J.P. Li, U. Lindahl, D. Spillmann, C. Betsholtz and H. Gerhardt, unpublished work). These two knockout strains display variously disordered HS structures that could be related to different vascular phenotypes. The results prompted us to define the structural features of HS required for the binding of PDGF-B. Assessing different HS-related oligosaccharide libraries in growth factor binding failed to implicate any unique HS sequence, but pointed to the importance of distribution and overall sulphation level of saccharide domains. Regulation of the overall sulphation of the HS chain may thus be an efficient and effective mechanism to control PDGF presentation. Thus for the first time our studies demonstrate a critical role played by HS in pericyte recruitment.


  • Cytokine–Proteoglycan Interactions: Biology and Structure: Biochemical Society Focused Meeting held at Royal Holloway University of London, Egham Hill, U.K., 9–10 January 2006. Organized and edited by B. Mulloy (NIBSC, U.K.) and C. Rider (Royal Holloway University of London, U.K.).

Abbreviations: ECM, extracellular matrix; HS, heparan sulphate; HSPG, HS proteoglycan; PDGF, platelet-derived growth factor; PDGFR, β, PDGF receptor β


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