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.

HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2

“…HSPGs are expressed on the EC surface where they act as low-affinity receptors for circulating growth factors and chemokines (26). HSPGs were found to critically regulate angiogenesis by facilitating cell-surface binding of various proangiogenic molecules (27). Recent data showed that p17 is a heparin/heparan sulfate-binding protein (28).…”

“…A recent study pointed to the capability of p17 to bind to HSPGs (28) and HSPGs are known to play a proangiogenic role depending on heparan sulfate fine structure (26,27). However, treatment of HUVECs with heparinase II to remove HSPGs did not influence the ability of p17 to form capillary-like structures.…”

Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia

“…To gain insight into the molecular mechanism underlying the angiogenic defect in Ndst1 ECKO mice, we initially speculated that endothelial Ndst1 deficiency might disrupt VEGF signaling, based on our previous findings that endothelial Ndst1 deletion attenuates VEGF signaling in tumor angiogenesis (9,14). However, examination of VEGFR2 phosphorylation found no significant difference between Ndst1 ECKO and Ndst1 f/f diaphragm at E18.5 ( Figure 4A).…”

The Synaptic Proteins β-Neurexin and Neuroligin Synergize With Extracellular Matrix-Binding Vascular Endothelial Growth Factor A During Zebrafish Vascular Development

“…A perturbation of HSPGs can result in a variation of morphogen gradients in ECM or alternatively it can interfere with stabilization of signaling complexes. 43 To test this hypothesis, we perturbed the overall HSPGs maturation by injecting a previously published MO targeting HS6ST2 34 . Sulphotransferases contribute to the heterogeneity of heparan sulphates and ECM maturation, which is essential for the modulation of ligand-receptor binding.…”