Endomucin restores depleted endothelial glycocalyx in the retinas of streptozotocin‐induced diabetic rats

Abstract

Endothelial glycocalyx plays a significant role in the development and progression of diabetic complications. Endomucin (EMCN) is an anti-inflammatory membrane glycoprotein that is mainly expressed in venous and capillary endothelial cells. However, the function of EMCN in diabetic retinopathy (DR) progression is still completely unknown. We first investigated the change of EMCN expression in the retina and human retinal microvascular endothelial cells. We then overexpressed EMCN in the retina with adeno-associated virus and induced DR with streptozotocin (STZ). We analyzed EMCN's effect on the integrity of endothelial glycocalyx under conditions of DR. Furthermore, we investigated EMCN's protective effect against inflammation and blood-retinal barrier (BRB) destruction. We found that EMCN is specifically expressed in retinal endothelial cells and that its levels are decreased during hyperglycemia in vitro and in vivo. Overexpression of EMCN can restore the retinal endothelial glycocalyx of STZ-induced diabetic rats. Furthermore, EMCN overexpression can decrease leukocyte-endothelial adhesion to ameliorate inflammation and stabilize the BRB to inhibit vessel leakage in rats with DR. EMCN may protect patients with diabetes from retinal vascular degeneration by restoring the endothelial glycocalyx. EMCN may thus represent a novel therapeutic strategy for DR because it targets endothelial glycocalyx degradation associated with this disease.

The Pathological Relevance of Increased Endothelial Glycocalyx Permeability

“…53 In streptozocin-induced diabetic rats, retinal permeability was also increased (measured by fluorescein isothiocyanateedextran accumulation in retinal tissue). 54 In the same study, overexpression of endomucin prevented damage to the endothelial glycocalyx, reduced leukocyte adhesion, and reduced retinal vessel permeability. 54 A reduction in tight junctions within the interendothelial cleft of retinal vessels has also been reported early in diabetic disease, making the direct contribution of glycocalyx injury impossible to assess.…”

“…54 A reduction in tight junctions within the interendothelial cleft of retinal vessels has also been reported early in diabetic disease, making the direct contribution of glycocalyx injury impossible to assess. 54,55 However, it seems likely that glycocalyx injury is contributing to the pathogenesis of DR through direct increases in permeability and by facilitating leukocyte adhesion; glycocalyx preservation therefore remains a promising therapeutic option. 54…”

“…54,55 However, it seems likely that glycocalyx injury is contributing to the pathogenesis of DR through direct increases in permeability and by facilitating leukocyte adhesion; glycocalyx preservation therefore remains a promising therapeutic option. 54…”

Research progress on the structure and function of endomucin

“…Endomucin is also expressed in retinal endothelial cells, and the expression level is reduced under high blood glucose in vitro and in vivo. Its overexpression can restore the glycocalyx of retinal endothelial cells induced by streptozotocin in diabetic rats 11 . In addition to reducing the adhesion of leukocytes to endothelial cells, overexpression of endomucin can also reduce inflammation, stabilize the blood‐retinal barrier, and inhibit vascular leakage 12 .…”

Roles of Endovascular Calyx Related Enzymes in Endothelial Dysfunction and Diabetic Vascular Complications

“…Experiments showed that vitamin D (Garsen et al, 2015), atlasacetam (Boels et al, 2016), and hypericin (An et al, 2017) can reduce damage to the endothelial glycocalyx by inhibiting heparanases. Diabetes can cause increased expression of TNF-α, IL-1β, and NF-LB p65 phosphorylation (Niu et al, 2019). When inflammation occurs, proinflammatory factors (TNF-α) activate vascular endothelial cells, P-and E-selectin expression increases, leukocytes begin to roll and attach to endothelial cells, and chemokines on endothelial cells start to activate leukocytes (Singh et al, 2011;Pahwa et al, 2016).…”