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Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling. <i>Egln1^Tie2Cre</i> mice with <i>Tie2Cre</i>-mediated deletion of Egln1, which encodes hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2), is the only mouse model with severe PAH, progressive occlusive pulmonary vascular remodeling, and right-sided heart failure leading to 50–80% mortality from the age of 3–6 months, indicating that the <i>Egln1^Tie2Cre</i> mice model is a long-sought-after murine PAH model. However, it is unknown if <i>Egln1^Tie2Cre</i> mice respond to FDA-approved PAH drugs in a way similar to PAH patients. Here, we tested the therapeutic effects of the three vasodilators: sildenafil (targeting nitric oxide signaling), ambrisentan (endothelin receptor antagonist), and treprostinil (prostacyclin analog) on <i>Egln1^Tie2Cre</i> mice. All of them attenuated right ventricular systolic pressure (RVSP) in <i>Egln1^Tie2Cre</i> mice consistent with their role as vasodilators. However, these drugs have no beneficial effects on pulmonary arterial function. Cardiac output was also markedly improved in <i>Egln1^Tie2Cre</i> mice by any of the drug treatments. They only partially improved RV function and reduced RV hypertrophy and pulmonary vascular remodeling as well as improving short-term survival in a drug-dependent manner. These data demonstrate that <i>Egln1^Tie2Cre</i> mice exhibit similar responses to these drugs as PAH patients seen in clinical trials. Thus, our study provides further evidence that the <i>Egln1^Tie2Cre</i> mouse model of severe PAH is an ideal model of PAH and is potentially useful for enabling identification of drug targets and preclinical testing of novel PAH drug candidates.