Endothelial barrier reinforcement relies on flow-regulated glycocalyx, a potential therapeutic target

Abstract

BACKGROUND: The onset of many disease processes depends on the function of the endothelial cell (EC) glycocalyx (GCX) which acts as a flow-dependent barrier to cellular infiltration and molecular transport across the blood vessel wall. OBJECTIVE: This review aims to examine these processes with the potential end goal of implementing GCX repair to restore EC barrier function and slow the progression of disease. METHODS: Cell and mouse studies were employed to examine the state of EC GCX in healthy versus disruptive flow conditions. Correlates of observations of the GCX with a number of EC functions were sought with an emphasis on studies of trans-endothelial barrier integrity against vessel wall infiltration of cells and molecules from the circulation. To demonstrate the importance of GCX as a regulator of trans-endothelial infiltration, assays were performed using ECs with an intact GCX and compared to assays of ECs with an experimentally degraded GCX. Studies were also conducted of ECs in which a degraded GCX was repaired. RESULTS: In healthy flow conditions, the EC GCX was found to be thick and substantially covered the endothelial surface. GCX expression dropped significantly in complex flow conditions and coincided with a disease-like cellular and molecular accumulation in the endothelium or within the blood vessel wall. Therapeutic repair of the GCX abolished this accumulation. CONCLUSIONS: Regenerating the degraded GCX reverses EC barrier dysfunction and may attenuate the progression of vascular disease.

Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction

“…The endothelial GCX is a transmembrane, proteoglycanglycoprotein layer extending from the luminal surface of ECs with a reported thickness ranging from 20 nm to 11 mm in vitro and in vivo, depending on the size and location of the vessel, as well as the method of GCX preservation and visualization ( Figure 5; Chignalia et al, 2016;Mitra et al, 2017;Harding et al, 2019). Due to its position, the GCX serves as a barrier to vascular permeability (Butler et al, 2020), can regulate the movement and absorption of blood-borne molecules, and can even affect the resistance to blood flow (Mitra et al, 2017;Zhu et al, 2018).…”

Endothelial dysfunction in neuroprogressive disorders—causes and suggested treatments

“…However, in atheroprone areas of arterial branches and bends, denuded levels of glycolax [ 93 ], decreased activity of manganese superoxide dismutase (MnSOD) [ 94 ] and low or oscillatory blood flow induce a chronic inflammatory state in resident ECs via the initial upregulation of JNK, p38 MAPK, RelA, IKK, p65 and ultimately the persistent activation of NF-κB [ 95 – 99 ], reviewed in [ 100 ].…”

Endothelial cells, neutrophils and platelets: getting to the bottom of an inflammatory triangle

“…Endothelial dysfunction is a complex phenomenon involving heightened ROS production, altered nitric oxide (NO) production and disruptions to vascular tone; production of MMPs and pro-inflammatory cytokines; and upregulation of cell adhesion molecules such as E-selectin, P-selectin and intracellular adhesion molecule-1 (ICAM-1) [4,5,33,34]. MMPs and ROS facilitate glycocalyx degradation and shedding, causing impaired mechanosensing and altering cell behaviour [22,28,35] to enable immune cell capture and trafficking [26,[36][37][38][39]. Compromised mechanosensing can in turn perpetuate reductions in shear-sensitive NO secretion and augment vascular permeability.…”

“…Under healthy conditions, the glycocalyx exists in dynamic equilibrium with circulating blood, changing its composition and thickness in response to haemodynamic forces and cues from soluble factors [ 26 ] in order to maintain equilibrium between hydrostatic and oncotic forces in the vessel [ 27 ]. Changes to the rheological environment are detected by the glycocalyx [ 28 ] and transduced to the underlying endothelium via actin anchoring. The actin cytoskeleton and the glycocalyx exist in a dynamic equilibrium with one another, each being modified in response to changes in the other to control endothelial barrier properties [ 29 , 30 ].…”