Targeting pulmonary arterial hypertension with aerobic training: anti-inflammatory and cardioprotective effects enhance survival in experimental models

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, increased right ventricular (RV) afterload, and high mortality. We investigated whether moderate aerobic training (AT) modulates inflammation, cardiopulmonary function, and survival in a monocrotaline (MCT)-induced PAH model. Male Wistar rats were randomized to nontrained (NT) or AT groups and treated with saline (SAL) or MCT: NT-SAL, NT-PAH, AT-SAL, and AT-PAH. AT consisted of treadmill exercise at ∼60% maximal oxygen consumption (V̇o_2max), 5 days/wk for 5 wk, starting 3 wk after PAH induction. Outcomes included cardiac function [echocardiography and pulmonary acceleration time (PAT)/pulmonary ejection time (PET)], lung mechanics, histology (Movat pentachrome, diffuse alveolar damage, and transmission electron microscopy), inflammatory biomarkers, and survival. Compared with NT-PAH, AT-PAH animals showed higher PAT/PET (<i>P</i> = 0.003), smaller RV area (<i>P</i> = 0.003), lower Fulton index (<i>P</i> = 0.002), and reduced hepatic congestion (<i>P</i> = 0.002). Lung elastance (<i>P</i> = 0.006), parenchymal collagen (<i>P</i> = 0.007), bronchoalveolar lavage fluid total cells (<i>P</i> = 0.04), and neutrophils (<i>P</i> < 0.001) were lower in AT-PAH. Pulmonary arterioles exhibited higher IL-10 and lower IL-4, TNF-α, and VEGF (all <i>P</i> < 0.001). Histology and ultrastructural analyses revealed reduced vascular remodeling, lower diffuse alveolar damage scores, and preserved lung and myocardial architecture (all <i>P</i> < 0.05). Survival was higher in AT-PAH (80% vs. 60%, <i>P</i> = 0.04). In conclusion, moderate AT before and after PAH induction improves RV-pulmonary artery coupling, reduces fibrosis and inflammation, preserves organ ultrastructure, and enhances survival. Integrating survival endpoints with noninvasive hemodynamics and dual-organ ultrastructural assessment provides mechanistic insight, supporting aerobic exercise as a potential nonpharmacological strategy in PAH. Further preclinical and clinical studies are needed to define optimal protocols and translational potential.<b>NEW & NOTEWORTHY</b> In just 5 wk, moderate aerobic training (AT) conferred a survival advantage in experimental pulmonary arterial hypertension (PAH), while simultaneously mitigating key pathological features, including right ventricular strain, pulmonary vascular remodeling, inflammation, and fibrosis. These coordinated, multisystem benefits were achieved through a practical, low-cost intervention, underscoring exercise capacity not only as a functional outcome but also as a potential prognostic indicator in PAH. Although highly promising, clinical translation remains premature and will require validation in additional preclinical models and well-designed clinical trials.