Pulmonary hypertension (PH) is a heterogeneous disorder associated with a progressive increase in pulmonary artery resistance and pressure. Although various therapies have been developed, the 5-year survival rate of PH patients still remains low. There is thus an important need to identify novel molecular networks involved in the pathogenesis of PH. In this study, we performed comparative transcriptome analysis of two mammalian PH models. In the one model, PH was caused by chronic hypoxia (Hx model). In the other model, PH was caused by the combination of a vascular endothelial growth factor receptor antagonist Sugen 5416 and chronic hypoxia (SuHx model). Intima and media proliferation and its consequent pulmonary vascular obstruction were prominent in SuHx model. Comparative transcriptome analysis revealed that five genes were significantly dysregulated in SuHx model and these genes might be regulated by Fos-related antigen-2（Fra-2）. The immunohistochemal analysis confirmed that the expression of Fra-2 were induced and localized within the cell nucleus in the pulmonary vascular lesions in SuHx model but not Hx model. These results suggest that Fra-2 may be involved in the pathophysiology of PH and a novel therapeutic target for the treatment of PH.