Reversal of experimental hypoxia-induced pulmonary hypertension by moderate exercise training in mice

Pulmonary hypertension (PH) is a progressive disease of multifactorial etiology, which has a poor prognosis and results in right heart dysfunction. The vascular pathology observed in PH is characterized by pulmonary vasoconstriction and abnormal vascular remodelling processes. If the disease is left untreated, patients typically develop right heart dysfunction, subsequently leading to right heart failure and death. Vasodilative therapy, including PDE-5 inhibitors, endothelin receptor-antagonists, prostanoids, or a combination thereof, is the current standard treatment for patients with PH. As the main symptoms of PH are shortness of breath and fatigue, exercise training has been considered as counterproductive in the past. Here we report that moderate physical training prevented pulmonary vascular disease in a mouse model of hypoxia-induced pulmonary hypertension. During 21 days of exposure to hypoxia mice that performed a daily training session on a treadmill five days a week in addition to daily treatment with Sildenafil, showed a significantly improved maximum walking distance compared to sedentary mice. Placebo-treated mice in hypoxia that performed regular training showed a significant increase of VO₂ max. This effect was similar to the effect of Sildenafil. RVSP, measured continuously by telemetry, was reduced to a healthy level in placebo-treated trained mice, and small vessel muscularization was reduced to a similar degree as with Sildenafil-treatment only. Hypoxia-induced upregulation of PDE5 in whole-lung homogenate did not occur in lungs of mice that performed daily exercise training, suggesting a role for PDE5 in the curative effect of exercise training. We conclude that moderate daily exercise should be included in up-to-date medical treatment strategies for patients with PH and may in some cases replace medication in the early stage of the disease.