Glycocalyx Degradation and Endothelial Dysfunction in Vaso-Occlusion: A Review

Abstract

The endothelial glycocalyx is a crucial component of vascular homeostasis, acting as a protective barrier and regulator of endothelial function. In sickle cell anemia (SCA), the degradation of the glycocalyx significantly contributes to endothelial dysfunction and the pathogenesis of vaso-occlusive crises (VOCs). This review examines the mechanisms of glycocalyx degradation, including the roles of shear stress, enzymatic activity, and oxidative stress. The breakdown of the glycocalyx leads to increased vascular permeability, enhanced cell adhesion, and impaired nitric oxide (NO) production, all of which exacerbate endothelial dysfunction and promote VOCs. Mechanistically, shear stress and mechanical forces from altered hemodynamics in SCA disrupt the glycocalyx. Enzymes like heparanase, hyaluronidase, and matrix metalloproteinases degrade glycocalyx components, while oxidative stress from chronic inflammation and hemolysis further accelerates this process. The resulting endothelial dysfunction manifests as increased permeability, promoting inflammation and cell adhesion, and reduced NO synthesis, leading to vasoconstriction and thrombosis. This pro-thrombotic environment facilitates the adhesion and aggregation of sickled red blood cells (RBCs) and other circulating cells, driving VOCs. Therapeutic strategies targeting glycocalyx preservation and restoration are critical for mitigating endothelial dysfunction in SCA. Approaches include the use of glycocalyx precursors, synthetic mimetics, antioxidant therapy, enzyme inhibitors, and nitric oxide donors. These therapies aim to restore the glycocalyx, reduce oxidative stress, and improve NO bioavailability, thereby reducing the incidence and severity of VOCs. Continued research into these therapeutic interventions is essential for optimizing treatment and improving clinical outcomes for patients with SCA. Keywords: Glycocalyx, Endothelial Dysfunction, Vaso-Occlusion, Sickle Cell Anemia, Inflammation, Shear Stress, Endothelial Cells