Endothelial heparan sulfate in angiogenesis

Abstract

Heparan sulfate (HS) is a linear polysaccharide composed of 50-200 glucosamine and uronic acid (glucuronic acid or iduronic acid) disaccharide repeats with epimerization and various sulfation modifications. HS is covalently attached to core proteins to form HS-proteoglycans. Most of the functions of HS-proteoglycans are mediated by their HS moieties. The biosynthesis of HS is initiated by chain polymerization and is followed by stepwise modification reactions, including sulfation and epimerization. These modifications generate ligand-binding sites that modulate cell functions and activities of proteinases and/or proteinase inhibitors. HS is abundantly expressed in developing and mature vasculature, and understanding its roles in vascular biology and related human diseases is an area of intense investigation. In this chapter, we summarize the significant recent advances in our understanding of the roles of HS in developmental and pathological angiogenesis with a major focus on studies using transgenic as well as gene knockout/knockdown models in mice and zebrafish. These studies have revealed that HS critically regulates angiogenesis by playing a proangiogenic role, and this regulatory function critically depends on HS fine structure. The latter is responsible for facilitating cell-surface binding of various proangiogenic growth factors that in turn mediate endothelial growth signaling. In cancer, mouse studies have revealed important roles for endothelial cell-surface HS as well as matrix-associated HS, wherein signaling by multiple growth factors as well as matrix storage of growth factors may be regulated by HS. We also discuss important mediators that may fine-tune such regulation, such as heparanase and sulfatases; and models wherein targeting HS (or core protein) biosynthesis may affect tumor growth and vascularization. Finally, the importance of targeting HS in other human diseases wherein angiogenesis may play pathophysiologic (or even therapeutic) roles is considered.

Fig. 1

HS structure and biosynthesis: Each sugar residue is depicted by a geometric symbol. Binding sites for ligands are defined by the arrangement of sulfate groups (NS, 2S, 3S, 6S) and uronic acid epimers (GlcA and IdoA). In mammals, as many as 26 enzymes (italicized) participate in the formation of HS chains. N-deacetylase/N-sulfotransferase (Ndst) initiates sulfation in clustered sites along HS chains, and isoenzymes 1 and 2 (of four expressed in mammals), highlighted in red, are expressed in ECs. Through the action of other sulfating enzymes, further sulfation modifications take place around sites of clustered N-sulfation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this chapter.)