Vessel wall BAMBI contributes to hemostasis and thrombus stability

Abstract

Key Points• This is the first report to describe the influence of BAMBI on both hemostasis and thrombus stability.• BAMBI present in the blood vessel wall (most likely the endothelium) rather than platelet BAMBI is required for thrombus stability.Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is a transmembrane protein related to the transforming growth factor-b superfamily, and is highly expressed in platelets and endothelial cells. We previously demonstrated its positive role in thrombus formation using a zebrafish thrombosis model. In the present study, we used Bambi-deficient mice and radiation chimeras to evaluate the function of this receptor in the regulation of both hemostasis and thrombosis. We show that Bambi 2/2 and Bambi 1/2 mice exhibit mildly prolonged bleeding times compared with Bambi 1/1 littermates. In addition, using 2 in vivo thrombosis models in mesenterium or cremaster muscle arterioles, we demonstrate that Bambi-deficient mice form unstable thrombi compared with Bambi 1/1 mice. No defects in thrombin generation in Bambi 2/2 mouse plasma could be detected ex vivo. Moreover, the absence of BAMBI had no effect on platelet counts, platelet activation, aggregation, or platelet procoagulant function. Similar to Bambi 2/2 mice, Bambitransplanted with Bambi 1/1 bone marrow formed unstable thrombi in the laser-induced thrombosis model that receded more rapidly than thrombi that formed in Bambi 1/1 mice receiving Bambi 2/2 bone marrow transplants.Taken together, these results provide strong evidence for an important role of endothelium rather than platelet BAMBI as a positive regulator of both thrombus formation and stability. (Blood. 2014;123(18):2873-2881

BAMBI Elimination Enhances Alternative TGF-β Signaling and Glomerular Dysfunction in Diabetic Mice

“…We used fully back-crossed mice on a C57BL/6 background, which develop only a mild phenotype ( 46 ), because we expected to see more pronounced changes in the BAMBI −/− mice because of their enhanced TGF-β signaling ( 30 , 32 , 33 ). Age-matched BAMBI +/+ and BAMBI −/− littermate mice were used; the BAMBI −/− mice had a slightly lower body weight at the time of DM induction, as previously observed ( 45 ) ( Table 1 ). Both BAMBI +/+ and BAMBI −/− mice developed comparable degrees of hyperglycemia after STZ injection over the 18-week study ( Fig.…”

“…Since glomerular BAMBI expression is suppressed in diabetic kidney disease and BAMBI −/− mice exhibit accentuated alternative TGF-β signaling and altered endothelial response after injury ( 30 , 31 , 45 ), we examined the pathogenic role of BAMBI deficiency in DN by comparing the development of diabetic glomerular injury in BAMBI −/− and BAMBI +/+ mice with STZ-induced diabetes. We used fully back-crossed mice on a C57BL/6 background, which develop only a mild phenotype ( 46 ), because we expected to see more pronounced changes in the BAMBI −/− mice because of their enhanced TGF-β signaling ( 30 , 32 , 33 ).…”

Conformational quiescence of ADAMTS‐13 prevents proteolytic promiscuity

“…Therefore, these models are unlikely to illustrate the full potential of GoF ADAMTS‐13 in thrombus resolution. In experimental 44, 45, 46 and human situations of pathological clot formation we anticipate that GoF ADAMTS‐13 will have increased efficacy compared with WT ADAMTS‐13 because of its dual antiplatelet and fibrinolytic functions.…”

Modeling Disorders of Blood Coagulation in the Zebrafish

“…Targeted screening in zebrafish of five predicted thrombocyte-expressed genes uncovered a previously unappreciated role for BAMBI (bone morphogenic protein and activin membrane-bound inhibitor) in laser-induced thrombus formation [72]. Subsequent studies in mice validated these results and determined that BAMBI expressed on the vessel wall, and not platelets, supports thrombus stability following laser-induced injury [73]. Zebrafish have also been used to validate potential mediators of thrombus formation identified from platelet mRNA expression profiling or genome-wide association studies (GWAS).…”