# Protective Treatments against Endothelial Glycos
## 1 Introduction  
The vascular endothelium plays several important roles including haemostatic balance, endothelial integrity, and blood flow regulation [1]. It comprises a single layer of endothelial cells, lining every blood vessel in the body and is understood to be 4000-7000 m\({}^{2}\)[2]. These cells play a vital role as a semipermeable membrane to allow the exchange of nutrients and the removal of waste to and from the blood. A key structure involved in these actions is the endothelial glycocalyx (EG), which coats cells' extracellular matrix. EG thickness ranges from 0.2 \(\upmu\)m in capillaries to 4.5 \(\upmu\)m in the carotid artery [3]. The glycocalyx enables changes by a process known as mechanotransduction. Mechanotransduction is the mechanism by which external mechanical stimuli are converted into cellular responses through signalling pathways [4]. The apical surface of the glycocalyx consists of glycosaminoglycans (GAGs); those commonly associated with the vasculature are heparan sulphate (HS), chondro sulphate (CS) and hyaluronic acid (HA) [5]. Additionally present are syndecans, which provide sites on the apical surface to highly regulate proteolytic cleavage. The best conceptual theory for glycocalyx to detectchanges in blood flow was described by [PERSON] [6] as the \"wind in the trees\". The wind (fluid flow) is sensed by the branches (GAGs) of which the drag force is transmitted through the trees/forest (glycocalyx) and stimulates a response. Twenty-four-hour exposure of fluid shear-stress (FSS) in an in vitro model of EG has been shown to enhance synthesis and distribution of the prevalent components (HS, CS, and HA) of the glycocalyx with nearly normal uniform spatial distribution, similar to baseline levels compared to only 30 min of exposure [7]. Surgery is associated with EG degradation [8]. A suggested mechanism for this is that the thickness of the glycocalyx, and thus the surface layer, is reduced by ischaemia/reperfusion [9]. This increases capillary permeability and, thereby, contributes to tissue oedema (Figure 1) [10]. EG degradation is known to disrupt the equilibrium between pro-inflammatory cytokines and adhesion molecules, and vasodilators and vasoconstrtors, leading to endothelial dysfunction [11]. Glycocalyx components are released, such as syndecan-1 and heparan sulphate, during surgery. However, the steps in which diseases, trauma, and surgery thin the EG are not well understood. [PERSON] et al. [12] undertook a prospective 75-patient double-blind cohort study and found trauma patients to have raised plasma syndecan-1 levels associated with 16 other markers for inflammation, and tissue and endothelial cell damage. Patients with significant EG degradation were shown to have a three-fold increase in mortality compared to those with lower syndecan-1 levels. A mechanism to explain the strong association between EG degradation and patients with trauma is through the extensive activation of the inflammatory and coagulation pathways. Protection against EG degradation could help treat against known diseases to shed major EG constituents, such as diabetes and hyperglyaemia, atherosclerosis and chronic kidney disease [13]. Recent studies have looked into pharmacological interventions to prevent EG degradation during surgery. With the limited studies, interventions have looked into two therapeutic routes: (1) dampening the inflammatory response and (2) fluid-therapy. (1) The EG plays an important role in the post-injury inflammatory response [14]. An increase in C-reactive protein (CRP) has been associated with a decreased thickness of the EG and  
Figure 1: EG structure during health (**left**) and degradation (**right**). Disease causes thinning of the glycocalyx. Glycocalyx constituents are released into the plasma. An inflammatory response is produced with the recruitment of leucocytes and the loss of fluid. impaired vasoreactivity [15]. (2) Infused fluid therapy has been associated with impaired microcirculation, resulting in tissue oedema.