Abstract 72: Endothelial Cell Tissue Factor Enhances Inflammation but Not Coagulation in Mouse Model of Sickle Cell Disease
Sickle cell disease (SCD) is associated with increased tissue factor (TF) expression and activation of coagulation. Using a mouse model of SCD, we have previously demonstrated that inhibition of TF with a rat-anti mouse TF (1H1) antibody not only abolishes activation of coagulation (measured by plasma levels of thrombin anti-thrombin (TAT) complexes) but also reduces inflammation and endothelial cell (EC) injury, which was indicated by attenuation of plasma levels of IL-6 and sVCAM-1, respectively. SCD is one of the few diseases where TF has been shown to be expressed on ECs. Therefore, we investigated the effect of EC-specific deletion of TF gene on activation of coagulation, inflammation and EC injury in a mouse model of SCD (BERK mice). Sickle cell (SS) mice that expressed normal levels of TF or have EC-specific deletion of TF gene (TFfl/flEC) were generated by transplanting TFfl/fl (normal expression of TF) and TFfl/fl Tie2 Cre+ mice (lacking TF gene in both hematopoietic cells and ECs) with bone marrow from SS mice (bone marrow transplantation reconstituted expression of TF in all hematopoietic cells in TFfl/fl Tie2 Cre+). Interestingly, we found that activation of coagulation (TAT) and EC injury (sVCAM-1) were not affected by EC-specific deletion of TF gene. In contrast, plasma levels of IL-6 were significantly reduced in TFfl/flEC SS mice compared to SS mice with normal levels of TF expression (mean+/-SEM; 6.9+/-1.8 vs 14.9+/-3.0 pg/ml; p<0.05). Similar results were observed in SS mice lacking protease activated receptor-2 (PAR-2) expression in all non-hematopoietic cells compared to SS mice expressing normal levels of PAR-2 (no difference in plasma levels of TAT and sVCAM-1; reduction of IL-6, 9.4+/-0.9 vs 18.9+/-4.5 pg/ml; p<0.05). In contrast, SS mice with PAR-1 deficiency in all non-hematopoietic cells demonstrated reduced plasma levels of sVCAM-1 (835+/-41 vs 1003+/-52 ng/ml; p<0.05) but not IL-6 or TAT. Our data indicates that increased expression of EC TF contributes to the inflammation (possibly via PAR-2 activation on ECs) whereas TF expressed by other cellular sources (monocytes,perivascular cells) contributes to the activation of coagulation and EC injury (likely via thrombin-dependent mechanisms) in this mouse model of SCD.
- © 2012 by American Heart Association, Inc.