Abstract
PurposeThe endothelial glycocalyx (GCX) plays a critical role in the health of the vascular system. Degradation of the GCX has been implicated in the onset of diseases like atherosclerosis and cancer because it disrupts endothelial cell (EC) function that is meant to protect from atherosclerosis and cancer. Examples of such EC function include interendothelial cell communication via gap junctions and receptor-mediated interactions between endothelial and tumor cells. This review focuses on GCX-dependent regulation of these intercellular interactions in healthy and diseased states. The ultimate goal is to build new knowledge that can be applied to developing GCX regeneration strategies that can control intercellular interaction in order to combat the progression of diseases such as atherosclerosis and cancer.MethodsIn vitro and in vivo studies were conducted to determine the baseline expression of GCX in physiologically relevant conditions. Chemical and mechanical GCX degradation approaches were employed to degrade the GCX. The impact of intact versus degraded GCX on intercellular interactions was assessed using cytochemistry, histochemistry, a Lucifer yellow dye transfer assay, and confocal, intravital, and scanning electron microscopy techniques.ResultsRelevant to atherosclerosis, we found that GCX stability determines the expression and functionality of Cx43 in gap junction-mediated EC-to-EC communication. Relevant to cancer metastasis, we found that destabilizing the GCX through either disturbed flow-induced or enzyme induced GCX degradation results in increased E-selectin receptor-mediated EC-tumor cell interactions.ConclusionOur findings lay a foundation for future endothelial GCX-targeted therapy, to control intercellular interactions and limit the progression of atherosclerosis and cancer.
Highlights
WHY STUDY GLYCOCALYX-MEDIATED INTERCELLULAR INTERACTIONS?Atherosclerotic cardiovascular disease and cancer are the two leading causes of death[117] and are responsible for 50% of deaths worldwide annually.[11]
Reported in a recent paper,[71] this study provides an improved understanding of the effect of GCX degradation on the attachment of cancer cells to the endothelium, which is very much needed for creating therapeutic measures that will combat the spread of cancer via strengthening of GCX against GAG degrading cytokines released by cancer tumors
The role of GCX in regulating intercellular interactions has been understudied, the recent work published by our group proves that there is a correlation between the structural integrity of the GCX and the performance of intercellular interaction proteins like Cx43 and E-selectin.[69,70,71,107]
Summary
WHY STUDY GLYCOCALYX-MEDIATED INTERCELLULAR INTERACTIONS?Atherosclerotic cardiovascular disease and cancer are the two leading causes of death[117] and are responsible for 50% of deaths worldwide annually.[11]. 1f and 1g), a fundamental vascular control mechanism of great importance in health and disease, and endothelial cell remodeling in response to shear stress (alignment and elongation in the direction of shear).[29] In a third study, which served as a platform for me to mentor one of John’s many undergraduate research assistants, Solomon Mensah (see his reflection below), we used a preclinical animal model to show that GCX shedding initiated by inflammation facilitates vessel wall infiltration and retention of lipids and other components that contribute to the development of atherosclerotic plaques
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