Figure 7.

The Endothelial Glycocalyx (ecGCx). This illustration depicts the normal components of the ecGCx: a unique extracellular matrix. The ecGCx in T2DM, LOAD and Long COVID/PASC is the first component of the endothelial cell (EC) that comes into contact with the blood components of the vascular lumen. The normal components of the ecGCx include two classes of proteins that are mostly anchored proteoglycans (PGN) (purple), glycoproteins (GP) (green) and Hyaluronic acid—Hyaluronan (HA) (blue) that is an exceedingly long polymer of disaccharides that are non-sulfated glycosaminoglycans. HA may be either unattached—free floating or anchored to CD44 on the plasma membrane of ECs, or form HA–HA complexes. HA may also reversibly interact at the lumen with plasma-derived albumin, fibrinogen and soluble PGNs. The PGNs and GPs side chains consist of glycosaminoglycans (GAGs), which are covalently bound to their core proteins and are highly sulfated, which are important for giving the ecGCx its net-negative charge. The two primary PGNs are the syndecans and glypicans. The GPs consist primarily of selectins (P and E), integrins (alpha v and beta 3) and the immunoglobulin superfamily of ICAM-1, VE-CAM and PE CAM-1. Caveolae are invaginations of lipid rafts on the EC plasma membrane and contain CD44 important to anchor glycosylphosphatidylinositol (GPI) that anchor glypican-1. The GPI/glypican-1 interaction is thought to activate endothelial nitric oxide synthase (eNOS) to produce bioavailable nitric oxide (NO) via the calcium calmodulin dependent Caveolin-1 (Cav-1) protein. Note on the right-hand side of this image the numerous causes for the attenuation/shedding or loss of the ecGCx. Note that Hcy is included since it is elevated in both T2DM and Late onset Alzheimer’s disease (LOAD). Hcy may compromise the ecGCx due to its elevation, which results in hyperhomocysteinemia (HHcy), oxidative stress with elevation in reactive oxygen nitrogen species (RONS), inflammation and activation of matrix metalloproteinases. Note that T2DM is known to increase hyaluronidase. The impaired FOCM with hyperhomocyteinemia, oxidative stress and inflammation can be damaging to the ecGCx and contribute to endothelial cell activation and dysfunction with detrimental effects on the vascular tissue that predispose to increased vascular inflammation and a prothrombotic state and ischemia, which is also an inducer of ecGCx loss. Image provided by CC 4.0 [48]. A = albumin; AGE/RAGE = advanced glycation end products and receptor to AGE; N = nucleus; ATPIII GP = antithrombin three glycoprotein; BEC = brain endothelial cell or just endothelial cell; BM = basement membrane; CAD = cadherin; CAM = cellular adhesion molecule; CD44 = cluster of differentiation 44; ecSOD = extracellular superoxide dismutase; F = fibrinogen; FGF2 = fibroblast Growth Factor 2; FOCM = folate-mediated one-carbon metabolism; GCx = glycocalyx; ICAM-1 = intercellular adhesion molecule; Ox LDL = oxidized low-density lipoprotein; LPL = lipoprotein lipase; MMPs = matrix metalloproteinases; N = nucleus; Na⁺ = sodium; O = orosomucoids; Pc = vascular mural cell pericyte(s); PECAM-1 = platelet endothelial cell adhesion molecule-1. RONS = reactive oxygen species; TFPI = tissue factor pathway inhibitor; TJ/AJ = tight and adherens junctions; VCAM = Vascular cell adhesion protein; VE CAD = vascular endothelial cadherins; VEGF = vascular endothelial growth factor; XOR = xanthine oxioreductase.