Glycocalyx in Atherosclerosis-Relevant Endothelium Function and as a Therapeutic Target

Abstract

Purpose of ReviewThe cell surface-attached extracellular glycocalyx (GCX) layer is a major contributor to endothelial cell (EC) function and EC-dependent vascular health and is a first line of defense against vascular diseases including atherosclerosis. Here, we highlight our findings regarding three GCX-dependent EC functions, which are altered when GCX is shed and in atherosclerosis. We discuss why the GCX is a viable option for the prevention and treatment of atherosclerosis.Recent FindingsGCX regulated EC activities such as barrier and filtration function, active cell-to-cell communication, and vascular tone mediation contribute to function of the entire vascular wall. Atheroprone vessel regions, including bifurcation sites, exhibit breakdown in GCX. This GCX degradation allows increased lipid flux and thereby promotes lipid deposition in the vessel walls, a hallmark of atherosclerosis. GCX degradation also alters EC-to-EC communication while increasing EC-to-inflammatory cell interactions that enable inflammatory cells to migrate into the vessel wall. Inflammatory macrophages and foam cells, to be specific, appear in early stages of atherosclerosis. Furthermore, GCX degradation deregulates vascular tone, by causing ECs to reduce their expression of endothelial nitric oxide synthase (eNOS) which produces the vasodilator, nitric oxide. Loss of vasodilation supports vasoconstriction, which promotes the progression of atherosclerosis.SummaryCommon medicinal atherosclerosis therapies include lipid lowering and anti-platelet therapies. None of these treatments specifically target the endothelial GCX, although the GCX is at the front-line in atherosclerosis combat. This review demonstrates the viability of targeting the GCX therapeutically, to support proper EC functionality and prevent and/or treat atherosclerosis.

Metastatic cancer cell attachment to endothelium is promoted by endothelial glycocalyx sialic acid degradation

“…GCX covers most mammalian cells. For endothelial cells (ECs), a healthy GCX forms a selective barrier between ECs and their neighboring environment, by blocking adhesion receptors on the endothelium from binding to ligands on cells and certain molecules from the environment (Figure a) . The EC GCX is composed of a variety of sugar chains, glycoproteins, and soluble proteins.…”

“…The EC GCX is composed of a variety of sugar chains, glycoproteins, and soluble proteins. For example, the GCX includes core proteins on which heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA) glycosaminoglycan sugar chains are attached . HS is the most abundant GCX component.…”

comparative effects of high fat diet or disturbed blood flow on glycocalyx integrity and vascular inflammation

“…The endothelial dysfunction and atherosclerosis propensity have been attributed to GCX thinning that has been noted to occur 5 . Van den Berg et al 6 showed thinned endothelial GCX at the bifurcation region of a mouse internal carotid artery compared to the common carotid artery 2 . Additionally, they showed that impaired barrier properties of GCX contribute to enhanced pro-atherogenic low density lipoprotein (LDL) accumulation in the intima at the carotid artery bifurcation 7 .…”

“…The endothelial glycocalyx (GCX) acts as a buffer between the endothelium surface and blood flow-derived shear forces and contributes to vascular barrier functionality, limiting leakage of fluid and macromolecules across the endothelial cell layer. The endothelial GCX is a negatively charged, heavily hydrated, heterogeneous polysaccharide mesh layer located on the inner lumen, bound to the endothelial cells' membranes [1][2] . It largely consists of cell-linked glycosaminoglycans including heparan sulfate, hyaluronic acid, sialic acid, and chondroitin sulfate 3 .…”

“…There is a large body of evidence showing the impact and influence of flow on the GCX. For instance, along vessel walls exposed to uniform blood and in relatively good health, the GCX has been shown to be robust and thus protective of the endothelium 2,4 . In geometrically complex vasculature, vessel walls are exposed to non-uniform flow patterns with low wall shear stresses due to blood recirculation.…”