Melatonin long-lasting beneficial effects on pulmonary vascular reactivity and redox balance in chronic hypoxic ovine neonates

Pulmonary arterial hypertension of the neonate (PAHN) is a pathophysiological condition characterized by maladaptive pulmonary vascular remodeling and abnormal contractile reactivity. This is a multifactorial syndrome with chronic hypoxia and oxidative stress as main etiological drivers, and with limited effectiveness in therapeutic approaches. Melatonin is a neurohormone with antioxidant and vasodilator properties at the pulmonary level. Therefore, this study aims to test whether a postnatal treatment with melatonin during the neonatal period improves in a long-lasting manner the clinical condition of PAHN. Ten newborn lambs gestated and born at 3600 m were used in this study, five received vehicle and five received melatonin in daily doses of 1 mg kg⁻¹ for the first 3 weeks of life. After 1 week of treatment completion, lung tissue and small pulmonary arteries (SPA) were collected for wire myography, molecular biology, and morphostructural analyses. Melatonin decreased pulmonary arterial pressure the first 4 days of treatment. At 1 month old, melatonin decreased the contractile response to the vasoconstrictors K⁺, TX₂, and ET-1. Further, melatonin increased the endothelium-dependent and muscle-dependent vasodilation of SPA. Finally, the treatment decreased pulmonary oxidative stress by inducing antioxidant enzymes and diminishing pro-oxidant sources. In conclusion, melatonin improved vascular reactivity and oxidative stress at the pulmonary level in PAHN lambs gestated and born in chronic hypoxia.