Glycocalyx disruption, endothelial dysfunction and vascular remodeling as underlying mechanisms and treatment targets of chronic venous disease.

Abstract

The glycocalyx is an essential structural and functional component of endothelial cells. Extensive hemodynamic changes cause endothelial glycocalyx disruption and vascular dysfunction, leading to multiple arterial and venous disorders. Chronic venous disease (CVD) is a common disorder of the lower extremities with major health and socio-economic implications, but complex pathophysiology. Genetic aberrations accentuated by environmental factors, behavioral tendencies, and hormonal disturbances promote venous reflux, valve incompetence, and venous blood stasis. Increased venous hydrostatic pressure and changes in shear-stress cause glycocalyx injury, endothelial dysfunction, secretion of adhesion molecules, leukocyte recruitment/activation, and release of cytokines, chemokines, and hypoxia-inducible factor, causing smooth muscle cell switch from contractile to synthetic proliferative phenotype, imbalance in matrix metalloproteinases (MMPs), degradation of collagen and elastin, and venous tissue remodeling, leading to venous dilation and varicose veins. In the advanced stages of CVD, leukocyte infiltration of the vein wall causes progressive inflammation, fibrosis, disruption of junctional proteins, accumulation of tissue metabolites and reactive oxygen and nitrogen species, and iron deposition, leading to skin changes and venous leg ulcer (VLU). CVD management includes compression stockings, venotonics, and surgical intervention. In addition to its antithrombotic and fibrinolytic properties, literature suggests sulodexide benefits in reducing inflammation, promoting VLU healing, improving endothelial function, exhibiting venotonic properties, and inhibiting MMP-9. Understanding the role of glycocalyx, endothelial dysfunction, and vascular remodeling should help delineate the underlying mechanisms and develop improved biomarkers and targeted therapy for CVD and VLU.