Structural diversity in the membrane lipids is essential for proper function of eukaryotic membranes. Sphingolipids, named after the mythical Sphinx due to their enigmatic physicochemical properties, are critical for specialized membrane microdomains such as rafts and caveolae. In higher organisms, sphingolipid metabolites, such as sphingosine, sphingosine 1-phosphate (S1P), and ceramide are utilized in intracellular metabolism, signaling, and extracellular cell–cell communication events. Sphingolipids are particularly important for the mammalian vascular system, in which plasma levels of S1P are several orders of magnitude higher than tissue levels, thereby constituting a vascular S1P gradient. S1P is a major regulator of vital endothelial cell (EC) functions including vascular permeability, vascular stabilization/maturation, angiogenesis, vascular tone control, nitric oxide (NO) synthesis, and survival. The endothelium produces and responds to S1P. Indeed S1P receptors in ECs are dynamically induced and regulated. Thus, sphingolipids (sphingomyelin [SM], sphingosine, ceramide, S1P, as well as numerous glycosphingolipid [GSL] species) constitute a major class of molecules involved in the structure and function of the endothelium (Table 45–1). Further knowledge in this area promises to provide novel therapeutic approaches in the restoration of endothelial health, a vital phenomenon compromised in many human maladies.

SPHINGOLIPID METABOLISM

Sphingolipids, which are built from the sphingosine base, are major structural components of the biological membranes of all eukaryotes. Both GSLs and SM belong to this class of lipids. Sphingolipids are localized on specialized domains of the membranes (1). For example, SM and GSL are essential constituents of membrane rafts. SM contains the sphingosine backbone, a fatty-acid side chain that is linked via the amide bond, and the amphipathic phosphocholine headgroup. Most SM species contain saturated or trans monounsaturated fatty acids with 16 to 24 carbons.