Modulation of vascular remodeling and vasoconstriction by α-phellandrene in hypoxia-induced pulmonary hypertension

OBJECTIVES: This study investigated α-phellandrene (PE)'s therapeutic effects on hypoxia-induced pulmonary hypertension (HPH), with emphasis on pulmonary vasoconstriction and vascular remodeling. METHODS: A rat model of HPH was successfully established and then the hemodynamic indexes were assessed. HE and Masson's staining were performed to observe tissue morphological changes and fibrosis. Immunohistochemistry and immunofluorescence were used to quantify Collagen I/III, and alpha-smooth muscle actin (α-SMA). malondialdehyde, glutathione, superoxide dismutase, and glutathione peroxidase assays for antioxidant status. Western blotting to analyse the protein expression levels in lung tissue of HPH rats. KEY FINDINGS: Our results indicate that PE significantly mitigated HPH, as evidenced by reductions in right ventricular (RV) systolic pressure, RV hypertrophy (evaluated via the RV/BW ratio and Fulton index), and key structural changes. PE effectively diminished pulmonary vascular remodeling, demonstrated by decreased vascular wall thickness and area, along with downregulation of Collagen I/III and α-SMA expression. Mechanistically, the protective effects of PE were associated with modulation of the AKT/eNOS/sGC/PKG pathway, a critical regulator of vascular tone and remodeling, as well as a reduction in oxidative stress and apoptosis. CONCLUSION: These findings highlight that PE alleviates HPH through a multifaceted approach targeting vasoconstriction and vascular remodeling, underscoring its potential as a novel therapeutic agent.