| First Author | Lindsey S | Year | 2014 |
| Journal | J Thromb Haemost | Volume | 12 |
| Issue | 3 | Pages | 383-94 |
| PubMed ID | 24410994 | Mgi Jnum | J:332278 |
| Mgi Id | MGI:6840508 | Doi | 10.1111/jth.12490 |
| Citation | Lindsey S, et al. (2014) Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen-dependent signaling. J Thromb Haemost 12(3):383-94 |
| abstractText | BACKGROUND: We previously identified aryl hydrocarbon receptor (AHR) as a novel regulator of megakaryocytic differentiation and polyploidization and reported that AHR-null mice have approximately 15% fewer platelets than do wild-type mice, yet they exhibit a dramatic, unexplained bleeding phenotype. OBJECTIVES: The current work tests our hypothesis that AHR-null platelets are functionally deficient, contributing to the previously reported (yet unexplained) bleeding phenotype present in AHR-null mice. METHODS: AHR-null bone marrow was ex vivo differentiated with thrombopoietin with or without AHR ligands or AHR inhibitors and analyzed for degree of megakaryopoiesis and polyploidization. Platelet function of AHR-null mice was assessed with aggregation and spreading assays. Platelet signaling was examined using Western analysis and Rac activity assays. RESULTS: AHR ligands differentiate murine bone marrow-derived progenitors into polyploid megakaryocytes in the absence of thrombopoietin, and AHR inhibitors block thrombopoietin-induced megakaryocytic differentiation. Despite their responsiveness toward thrombin, AHR-null platelets demonstrate decreased aggregation and spreading in response to collagen compared with wild-type platelets. AHR-null platelets bind fibrinogen after stimulation with thrombin or AYPGKF and aggregate in response to AYPGKF and adenosine diphosphate. Mechanistically, AHR absence led to down-regulation of Vav1 and Vav3, altered phospholipase Cgamma2 phosphorylation, decreased Rac1 activation, and reduced platelet activation in response to collagen. CONCLUSIONS: These results are consistent with a role for AHR in platelet function, especially as it relates to platelet aggregation and spreading in response to collagen. Our work suggests AHR is a critical component of the physiologic response that platelets undergo in response to collagen and may provide novel treatment options for patients with bleeding disorders. |
