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. Fibrinogen-like protein 2 (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 endothelial cells and mediates multiple pathological processes. This implies that it may also play a role in PH. In this study, we examined the expression of FGL2 in idiopathic pulmonary arterial hypertension (IPAH) patients, and in monocrotaline-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 in 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 (proteinase-activated receptor 1) expression and decreased the overactivation 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. NEW & NOTEWORTHY This is the first study to demonstrate that fibrinogen-like protein 2 (FGL2) participates in the pathological progression of pulmonary hypertension (PH) in human idiopathic pulmonary arterial hypertension, a monocrotaline rat PH model, and a hypoxia mouse PH model. Genetic knockout of Fgl2 significantly limited the development of PH indicated by reduced in situ thrombosis, vascular remodeling, and endothelial dysfunction, and suppressed PAR1 (proteinase-activated receptor 1) signaling and overactivation of platelets on PH. These results suggest FGL2 presents a potential therapeutic target for clinical treatment of PH.
Systemic endothelial dysfunction in children with idiopathic pulmonary arterial hypertension correlates with disease severity
