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New chemical-enzymatic technology based on the modification of the bacterial polysaccharide K5 from Escherichia coli leads to the synthesis of a number of heparin/heparan sulfate-like molecules with different biological activities. With this technology, two families of sulfated compounds were synthesized, which differ in their uronic acid content. The first group contains only glucuronic acid, whereas the second group contains about 50% iduronic acid following epimerization by immobilized recombinant C5 epimerase. This has led to the development of various anticoagulant and nonanticoagulant K5 derivatives endowed with different – and sometimes highly specific – antitumor, antiviral, and/or anti-inflammatory activities.

Heparan sulfate is a linear polysaccharide composed of glucosamine and uronic acid (glucuronic acid or iduronic acid) disaccharide repeats with various types of sulfation modifications. More than 26 enzymes participate in the biosynthesis of heparan sulfate, which includes two major steps of chain polymerization and chain modification. The chain modification steps proceed sequentially but are incomplete, resulting in enormous structural diversity in mature heparan sulfate. In tissues, heparan sulfate covalently attaches to core proteins to form heparan sulfate proteoglycans, and are abundant at the cell surface and in the extracellular matrix. Studies have demonstrated that heparan sulfate interacts with growth factors, growth factor binding proteins, extracellular proteases, protease inhibitors, chemokines, morphogens, and adhesive proteins to critically regulate cell functions under both physiological and pathological conditions. In this chapter, I will review our current understanding of the cellular and molecular mechanisms, and the structure–function relationship of heparan sulfate in the regulation of inflammation and angiogenesis, with particular focus on the regulatory roles of heparan sulfate on the key inflammatory molecules, selectin and chemokine, and on the vascular endothelial growth factor, the master proangiogenic factor of angiogenesis.

Proteoglycans (PGs) form a complex and heterogeneous family of macromolecules, which are found in all mammalian tissues. They are particularly abundant in connective tissues (such as cartilage, skin, blood vessel wall) where the extracellular matrix is large and well developed. In these tissues, PGs represent the most important component of the interfibrillar ground substance and interact with collagen fibrils [1–3].

Heparin and heparan sulphate are sulphated polysaccharides present in connective tissue and on cell surfaces, either as the free carbohydrate (glycosaminoglycan) chain, or covalently bonded to protein as proteoglycans. They consist of alternating uronic acid and glucosamine residues, and are sulphated both at the O and N positions. Heparan sulphate contains less iduronic acid and has a lower sulphate content than heparin, but they should in fact be considered as a single class of glycosaminoglycan, including a continuous spectrum of molecules of differing uronic acid composition and degree of sulphation. Their structures are reviewed by Lindahl and Hook (1978), Hascall and Hascall (1981) and Hook et al. (1984).

So far, about 200 different species of archaebacteria and eubacteria from most phylogenetic branches have been identified to carry regularly arranged surface layers (S-layers) (Sleytr and Messner, 1983, Sleytr et al. 1986a). Thus, S-layers appear to be a universal rather than a unique feature of prokaryotic cells. Quantitative calculations have revealed that S-layers can account for up to 10% of the total cell protein and therefore represent the major cell protein.

The research on the mechanism of calcification has been inspired, since its beginning, by the hypothesis that calcium and phosphate ions precipitate to form the salt of skeletal tissues, wherever a local factor causes a decrease in the energy barrier of their combination (Sobel 1955).