exhibit abnormal angiogenesis with defective vessel branching.47,48 That vessel branching requires HSPGs is indicated by zebrafish studies showing angiogenic sprouting requiring the syndecan-2 core protein.49 Moreover, knock-in mice that express a perlecan core protein lacking HS chains exhibit defective FGF-stimulated angiogenesis.50 Mice lacking various HS modification enzymes have recently been generated. Deficiencies in C5-epimerase, NDST1, HS2ST and HS3ST1 alter HS structure and result in developmental defects that produce postnatal lethality.51−56 Given the multiple roles of HS, evaluation of adult functions will require mice with cell type-specific deficiencies. Indeed, mice in which only ECs are deficient for NDST1 have recently been generated. They have a reduced infiltration of neutrophil into tissues, which involves reduced EC presentation of lumenal surface chemokines to leukocytes, EC transcytosis of chemokines, and L-selectin-mediated binding of leukocytes to ECs.57 Thus, the involvement of specific HS structures in multiple aspects of vascular development and function should be revealed by future analyses of mice with global or cell typespecific deficiencies in HS modification enzymes.

6. HSPG Modulation of Ligand-Receptor Interactions

6.1.HSPGs are co-receptors that augment ternary complex formation

Multiple aspects of signaling involve HSPGs, which can serve as either positive or negative regulators (reviewed in Refs. 16 and 58). The various mechanisms have been most extensively established for the fibroblast growth factors (FGFs), which we review as a paradigm of how the HS chains of HSPGs operate in multiple fashions to regulate the activities of numerous heparin-binding growth factors.

As described in Chapter 3, FGF signaling involves a family of more than 20 ligands that activate five different tyrosine kinase receptors (FGFRs). The complexity of this system is further expanded by the existence of multiple splice variants for each FGFR. Signaling requires the formation of a ternary complex in which two FGFs bind and thereby dimerize two FGFRs. Receptor dimerization is essential for