A multitude of biological processes are regulated by heparan sulfate proteoglycans (HSPGs), which are produced by virtually all cell types. These hybrid molecules are composed of protein cores to which are attached one or more long chains of heparan sulfate (HS). Functional diversity is engendered in part from a multiplicity of core proteins and in part from the structural complexity of the HS chain. This polysaccharide is a type of glycosaminoglycan (GAG) – a long un branched copolymer comprised of alternating amino and acid sugars. The HS sugar residues are decorated at various positions with sulfate groups, which creates a large array of short sequence motifs that bind and thereby modulate the functional properties of numerous regulatory molecules, including signaling ligands/receptors, proteases, enzymes, and lipoproteins (Table 106–1) (1,2). HS– protein interactions control cellular processes such as signaling, adhesion, migration, and vesicular trafficking. Through these cellular actions, HSPGs regulate many biological events including angiogenesis, lipoprotein metabolism, inflammation, hemostasis, developmental inductions, and axonal guidance.

This chapter focuses on only one aspect of HSPG biology – the input role of the HS chain in regulating endothelial cell (EC) signaling by “heparin-binding growth factors.” For purposes of discussion, this term is defined as any signaling ligand that exhibits high affinity to heparin, a particular type of highly sulfated HS. This definition encompasses classic growth factors such as fibroblast growth factors (FGFs); vascular endothelial growth factors (VEGFs); heparin-binding epidermal growth factor (Wnts); cytokines like interleukin-3, granulocyte monocyte colony stimulating factor (GM-CSF), and interferon-γ; most chemokines; and even growth inhibitors such as endostatin. Thus, this term includes the majority of HS binding ligands (see Table 106–1).