The chondroitin sulfate moiety mediates thrombomodulin-enhanced adhesion and migration of vascular smooth muscle cells

Abstract

BackgroundThrombomodulin (TM), a transmembrane glycoprotein highly expressed in endothelial cells (ECs), is a potent anticoagulant maintaining circulation homeostasis. Under inflammatory states, TM expression is drastically reduced in ECs while vascular smooth muscle cells (VSMCs) show a robust expression of TM. The functional role of TM in VSMCs remains elusive.MethodsWe examined the role of TM in VSMCs activities in human aortic VSMCs stimulated with platelet-derived growth factor-BB (PDGF-BB). Using rat embryonic aorta-derived A7r5 VSMCs which do not express TM, the role of the chondroitin sulfate (CS) moiety of TM in VSMCs was delineated with cells expressing wild-type TM and the CS-devoid TM mutant.ResultsExpression of TM enhanced cell migration and adhesion/spreading onto type I collagen, but had no effect on cell proliferation. Knocking down TM with short hairpin RNA reduced PDGF-stimulated adhesion and migration of human aortic VSMCs. In A7r5 cells, TM-mediated cell adhesion was eradicated by pretreatment with chondroitinase ABC which degrades CS moiety. Furthermore, the TM mutant (TMS490, 492A) devoid of CS moiety failed to increase cell adhesion, spreading or migration. Wild-type TM, but not TMS490, 492A, increased focal adhesion kinase (FAK) activation during cell adhesion, and TM-enhanced cell migration was abolished by a function-blocking anti-integrin β1 antibody.ConclusionChondroitin sulfate modification is required for TM-mediated activation of β1-integrin and FAK, thereby enhancing adhesion and migration activity of VSMCs.Electronic supplementary materialThe online version of this article (10.1186/s12929-018-0415-7) contains supplementary material, which is available to authorized users.

Thrombin cleaves and activates the protease-activated receptor 2 dependent on thrombomodulin co-receptor availability

“…Furthermore, we found that exosite II blocking aptamers or exosite II binding heparin interfere with PAR2 cleavage by thrombin. These results are in accordance with a recently published study that links the TM glycosaminoglycan domain to immune responses [65].…”

The values of coagulation function in COVID-19 patients

“…PIC as a marker of fibrinolytic system activation, predicting the formation of thrombus, assisting the diagnosis of DIC, and guiding antifibrinolytic treatment [ 17 ]. The elevated level of TM indicates an impaired vascular endothelial system [ 18 , 19 ]. t-PAIC, key marker of fibrinolytic system, suggesting thrombus progression [ 20 , 21 ].…”

Distribution and Function of Glycosaminoglycans and Proteoglycans in the Development, Homeostasis and Pathology of the Ocular Surface

“…In normal human corneas there are 8 μg of CS/DS per mg dry weight with ∼40 disaccharides per chain, which decreases to ∼15 disaccharides in corneas affected by macular corneal dystrophies ( Plaas et al, 2001 ). CSPGs are important ECM components with diverse functions in tissues, such as regulating cell adhesion, cell growth, neuronal plasticity, neuronal regeneration and cell migration, and form the bulk of the majority of connective tissues ( Coulson-Thomas et al, 2008 , 2016 ; Silver et al, 2013 ; Silver and Silver, 2014 ; Smith et al, 2015 ; Gesteira et al, 2016 ; Pai et al, 2018 ; Pudełko et al, 2019 ).…”