TGF-β-Smad2/3 signaling in high-altitude pulmonary hypertension in rats: Role and mechanisms via macrophage M2 polarization.

Objective: Transforming growth factor beta (TGF-β) is a key regulator of macrophage polarization, yet its role in high-altitude pulmonary hypertension (HAPH) remains poorly understood. This study aimed to explore the effects of TGF-β on macrophage polarization under high-altitude conditions and elucidate the molecular mechanisms driving macrophage phenotypic changes in HAPH, with potential therapeutic implications. Methods: A HAPH rat model was established by exposing rats to a hypoxic environment simulating 5,000 m altitude for 4 weeks. Rats were prophylactically treated weekly with the TGF-β inhibitor SB-431542. Pulmonary artery pressure and right ventricular hypertrophy index were measured to confirm model establishment. Hematoxylin and eosin staining, immunohistochemistry, and western blotting were used to assess TGF-β-Smad2/Smad3 signaling and macrophage polarization. Results: The HAPH group showed significantly increased pulmonary artery pressure and right ventricular hypertrophy index compared to controls. These changes were associated with elevated M2 macrophage levels, increased anti-inflammatory cytokines (IL-4 and IL-10), and enhanced TGF-β and Smad2/Smad3 signaling. TGF-β inhibition reversed these effects. Conclusion: The TGF-β-Smad2/Smad3 pathway promotes macrophage M2 polarization, driving HAPH progression through anti-inflammatory cytokine release. Inhibiting this pathway reduces M2 polarization and alleviates HAPH in rats, highlighting its therapeutic potential.