Background and PurposePulmonary arterial hypertension (PAH) is a life‐threatening disease that leads to progressive pulmonary hypertension, right heart failure and death. Parenteral prostaglandins (PGs), including treprostinil, a prostacyclin analogue, represent the most effective medical treatment for severe PAH. We investigated the effect of treprostinil on established severe PAH and underlying mechanisms using the rat SU5416 (SU, a VEGF receptor‐2 inhibitor)‐chronic hypoxia (Hx) model of PAH.Experimental ApproachMale Sprague Dawley rats were injected with SU (20 mg·kg⁻¹, s.c.) followed by 3 weeks of Hx (10% O₂) to induce severe PAH. Four weeks post‐SU injection, baseline right ventricular (RV) systolic pressure (RVSP) was measured, and the rats were randomized to receive vehicle or treprostinil treatment (Trep‐100: 100 ng·kg⁻¹·min⁻¹ or Trep‐810: 810 ng·kg⁻¹·min⁻¹). Following 3 weeks of treatment, haemodynamic and echocardiographic assessments were performed, and tissue samples were collected for protein expression and histological analysis.Key ResultsAt week 7, no difference in RVSP or RV hypertrophy was observed between vehicle and Trep‐100; however, Trep‐810 significantly reduced RVSP and RV hypertrophy. Trep‐810 treatment significantly improved cardiac structure and function. Further, a short‐term infusion of treprostinil in rats with established PAH at 4 weeks post‐SU produced an acute, dose‐dependent reduction in RVSP consistent with a vasodilator effect. However, chronic Trep‐810 treatment did not alter media wall thickness, degree of vascular occlusion or total vessel count in the lungs.Conclusions and ImplicationsTreprostinil exerts therapeutic benefits in PAH through decreased vascular resistance and improved cardiac structure and function; however, treprostinil treatment does not have direct impact vascular remodelling.