| First Author | Giri H | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 11 | PubMed ID | 33836597 |
| Mgi Jnum | J:303258 | Mgi Id | MGI:6512874 |
| Doi | 10.1073/pnas.2022248118 | Citation | Giri H, et al. (2021) Thrombomodulin is essential for maintaining quiescence in vascular endothelial cells. Proc Natl Acad Sci U S A 118(11):e2022248118 |
| abstractText | Thrombomodulin (TM) is a thrombin receptor on endothelial cells that is involved in promoting activation of the anticoagulant protein C pathway during blood coagulation. TM also exerts protective anti-inflammatory properties through a poorly under-stood mechanism. In this study, we investigated the importance of TM signaling to cellular functions by deleting it from endothe-lial cells by CRISPR-Cas9 technology and analyzed the resultant phenotype of TM-deficient (TMâ/â) cells. Deficiency of TM in en-dothelial cells resulted in increased basal permeability and hyper- permeability when stimulated by thrombin and TNF-α. The loss of the basal barrier permeability function was accompanied by in-creased tyrosine phosphorylation of VE-cadherin and reduced po-lymerization of F-actin filaments at cellular junctions. A significant increase in basal NF-κB signaling and expression of inflammatory cell adhesion molecules was observed in TMâ/â cells that resulted in enhanced adhesion of leukocytes to TMâ/â cells in flow chamber experiments. There was also a marked increase in expression, stor-age, and release of the von Willebrand factor (VWF) and decreased storage and release of angiopoietin-2 in TMâ/â cells. In a flow chamber assay, isolated platelets adhered to TMâ/â cells, forming characteristic VWFâplatelet strings. Increased VWF levels and in-flammatory foci were also observed in the lungs of tamoxifen-treated ERcre-TMf/f mice. Reexpression of the TM construct in TMâ/â cells, but not treatment with soluble TM, normalized the cellular phenotype. Based on these results, we postulate cell-bound TM endows a quiescent cellular phenotype by tightly regulating expression of procoagulant, proinflammatory, and angiogenic molecules in vascular endothelial cells. |
