CD248 enhances tissue factor procoagulant function, promoting arterial and venous thrombosis in mouse models

Abstract

Background: CD248 is a pro-inflammatory, transmembrane glycoprotein expressed by vascular smooth muscle cells (VSMC), monocytes/macrophages, and other cells of mesenchymal origin. Its distribution and properties are reminiscent of those of the initiator of coagulation, tissue factor (TF).Objective: We examined whether CD248 also participates in thrombosis. Methods:We evaluated the role of CD248 in coagulation using mouse models of vascular injury, and by assessing its functional interaction with the TF-factor VIIa (FVIIa)factor X (FX) complex. Results:The time to ferric chloride-induced occlusion of the carotid artery in CD248 knockout (KO) mice was significantly longer than in wild-type (WT) mice. In an inferior vena cava (IVC) stenosis model of thrombosis, lack of CD248 conferred relative resistance to thrombus formation compared to WT mice. Levels of circulating cells and coagulation factors, prothrombin time, activated partial thromboplastin time, and tail bleeding times were similar in both groups. Proximity ligation assays revealed that TF and CD248 are <40 nm apart, suggesting a potential functional relationship.Expression of CD248 by murine and human VSMCs, and by a monocytic cell line, significantly augmented TF-FVIIa-mediated activation of FX, which was not due to differential expression or encryption of TF, altered exposure of phosphatidylserine or differences in tissue factor pathway inhibitor expression. Rather, conformationspecific antibodies showed that CD248 induces allosteric changes in the TF-FVIIa-FX complex that facilitates FX activation by TF-FVIIa. Conclusion:CD248 is a newly uncovered protein partner and potential therapeutic target in the TF-FVIIa-FX macromolecular complex that modulates coagulation.

No Significant Association Between Plasma Endosialin Levels and the Presence or Severity of Coronary Artery Disease

“…Thus, endosialin may play a role in the progression of atherosclerosis associated with inflammation and fibrosis. Furthermore, endosialin-knockout mice were reported to be protected against arterial thrombosis [6]. An immunofluorescence analysis also showed increased endosialin expression and infiltrating CD8 T cells in aortic aneurysm specimens, suggesting a role of endosialin in vascular remodeling [3].…”

“…Since endosialin is suggested to play a role in the progression of atherosclerosis [3,4,6], we hypothesized that plasma endosialin levels in patients with CAD would be high. Our present study is the first to report plasma endosialin levels in patients with CAD.…”

“…Endosialin expression is also low in normal perivascular cells. During inflammation and tumor progression, endosialin was shown to be upregulated in perivascular cells, adipocytes and some tumor cells [6][7][8]. In colon cancer, silencing endosialin inhibited the migration and proliferation of tumor-associated fibroblasts [9].…”

Tissue factor in cancer-associated thromboembolism: possible mechanisms and clinical applications

“…The cell-surface glycoprotein CD248 contributes to TF activation (Table 1 ) [ 80 ]. CD248 binds TF and changes the conformation of the TF–fVIIa-fX complex to activate fX in various cells in a decryption-independent manner [ 80 ]. Furthermore, CD248 facilitated ATE and VTE in CD248 -knockout mouse models [ 80 ].…”

“…CD248 binds TF and changes the conformation of the TF–fVIIa-fX complex to activate fX in various cells in a decryption-independent manner [ 80 ]. Furthermore, CD248 facilitated ATE and VTE in CD248 -knockout mouse models [ 80 ]. The importance of this mechanism in CAT is currently unclear.…”