Stabilin‐2 deficiency increases thrombotic burden and alters the composition of venous thrombi in a mouse model

Abstract

Background Stabilin‐2 is an endocytic scavenger receptor that mediates the clearance of glycosaminoglycans, phosphatidylserine‐expressing cells, and the von Willebrand factor‐factor VIII (FVIII) complex. In a genome‐wide screening study, pathogenic loss‐of‐function variants in the human STAB2 gene associated with an increased incidence of unprovoked venous thromboembolism (VTE). However, the specific mechanism(s) by which stabilin‐2 deficiency influences the pathogenesis of VTE is unknown. Objectives The aim of this study was to assess the influence of stabilin‐2 on deep vein thrombosis (DVT) and to characterize the underlying prothrombotic phenotype of stabilin‐2 deficiency in a mouse model. Methods DVT was induced using the inferior vena cava (IVC) stenosis model in two independent cohorts (littermates and non‐littermates) of wild‐type (Stab2+/+) and stabilin‐2 (Stab2−/−)–deficient mice. Thrombus structure and contents were quantified by immunohistochemistry. Plasma procoagulant activity was assessed and complete blood counts were performed. Results Incidence of thrombus formation was not altered between Stab2+/+ and Stab2−/− mice. When thrombi were formed, Stab2−/− mice developed significantly larger thrombi than Stab2+/+ controls. Thrombi from Stab2−/− mice contained significantly more leukocytes and citrullinated histone H3 than Stab2+/+ thrombi. Stab2−/− mice had increased FVIII activity. Circulating levels of monocytes and granulocytes were significantly elevated in Stab2−/− mice, and Stab2−/− mice had elevated plasma cell‐free DNA 24 hours post‐IVC stenosis compared to their Stab2+/+ counterparts. Conclusions These data suggest that stabilin‐2 deficiency associates with a prothrombotic phenotype involving elevated levels of neutrophil extracellular trap‐releasing leukocytes coupled with endogenous procoagulant activity, resulting in larger and qualitatively distinct venous thrombi.

11β-HSD1 inhibitor efficacy in type 2 diabetes is cortisol-dependent

“…For example, lower expression of pro-fibrotic POSTN and CILP (reduced by AZD4107 here) were associated with improved cardiac remodelling and function [30,31], whilst 11β-HSD1 inhibition also improved recovery following myocardial infarction in mice [31,32]. Further, we found that AZD4017 induced thromboprotective ADAMTS13, PROCR, STAB2, PLAU, and reduced prothrombotic SERPINE1, with differential expression of other coagulation genes (PROS1, PLAT, VWF, ST3GAL4, RUNX1) also suggesting a novel role for 11β-HSD1 in the regulation of haemostasis [33][34][35]. Other novel 11β-HSD1 targets include AZD4017-upregulated SOSTDC1; a TGF-beta inhibitor associated with endometrial receptivity [36], PIEZO2; a cation channel associated with mechanosensation and diabetic neuropathy [37,38], and key regulators of metabolism such as GPAT3 [39,40], STEAP4 [41], HMGCS2, and SOX4 [42].…”

Reduction of Stabilin-2 Contributes to a Protection Against Atherosclerosis

“…A recent report has demonstrated that vWF binds to STAB2 protein and is cleared by LSECs in humans ( 15 ). The GWAS Catalog lists significant association of SNPs in or near the STAB2 gene with circulating vWF and FVIII levels, and recent human and mouse studies indicate Stab2 is involved in venous thromboembolism ( 33 , 52 , 53 ). Increased plasma levels of vWF and FVIII have been shown to enhance platelet recruitment to endothelial cells ( 32 ).…”

Neutrophil extracellular traps mediate deep vein thrombosis: from mechanism to therapy

“…They believe this suppression is beneficial because it protects neutrophils from large interstitial shear stresses within occlusive thrombi ( 272 ). Stabilin-2 is an endocytic scavenger receptor that mediates the clearance of the von Willebrand factor-VIII complex (FVIII) and reduces the release of NETs and DVT formation ( 234 ). The incidence of DVT in FXI-deficient patients is relatively low, and research on FXI therapies regarding FXI is ongoing ( 200 ).…”