LAUSR

In situ thrombus formation is one of the major pathological features of pulmonary hypertension (PH). The mechanism of in situ thrombosis has not been clearly identified. Fgl2 prothrombinase is an immune coagulant that can cleave prothrombin to thrombin which then converts fibrinogen into fibrin. This mechanism triggers in situ thrombus formation directly, bypassing both the intrinsic and extrinsic coagulation pathways. Fgl2 prothrombinase is mainly expressed in endothelia cells and mediates multiple pathological processes. This implies it may also play a role in PH. In this study, we examined the expression of Fgl2 in IPAH patients, and in MCT-induced rat and hypoxia-induced mouse PH models. Fgl2-/-mice were used to evaluate the development of PH and explore associated pathological changes. These included in situ thrombosis, vascular remodeling and endothelial apoptosis. Following these analyses, we examined possible signaling pathways downstream of Fgl2 in PH. We show Fgl2 is upregulated in pulmonary vascular endothelium in human IPAH, and two animal PH models. Genetic knockout of Fgl2 limited the development of PH, indicated by decreased in situ thrombus formation, less vascular remodeling and reduced endothelial dysfunction. In addition, loss of Fgl2 downregulated Par1 expression and decreased the over-activation and consumption of platelets in hypoxia-induced PH. These results indicate Fgl2 participate in the development of PH and loss of Fgl2 could attenuate PH by reducing in situ thrombosis and suppressing Par1 signaling. Thus, we provide evidence that suggests Fgl2 prothrombinase presents a potential therapeutic target for clinical treatment of PH.