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.
Highlights
Thrombomodulin (TM), a transmembrane glycoprotein highly expressed in endothelial cells (ECs), is a potent anticoagulant maintaining circulation homeostasis
We previously found that platelet-derived growth factor (PDGF)-BB, the most potent mitogen and chemoattractant of vascular smooth muscle cells (VSMCs) in vitro, induces TM expression in VSMCs through Src kinase and PI3-kinase/Akt/mTOR-dependent signaling pathway
Our results indicate that TM expression promotes cell spreading, adhesion, and migration involving the activation of β1-integrin and focal adhesion kinase (FAK) and the chondroitin sulfate (CS) moiety is required for these processes
Summary
Thrombomodulin (TM), a transmembrane glycoprotein highly expressed in endothelial cells (ECs), is a potent anticoagulant maintaining circulation homeostasis. TM expression is drastically reduced in ECs while vascular smooth muscle cells (VSMCs) show a robust expression of TM. Migration and proliferation of vascular smooth muscle cells (VSMCs) are key events in the intimal thickening of atherosclerosis and neointimal formation induced by vascular injury [1]. VSMCs in the media transform from a quiescent, contractile phenotype into an activated, synthetic phenotype and migrate to the intima. Thrombomodulin (TM), a transmembrane glycoprotein in endothelial cells (ECs), is a critical player in maintaining vascular thromboresistance. TM acts as a cofactor in protein C activation through regulating thrombin substrate affinity and plays a critical role in the anticoagulant pathway [3].
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