Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia - 29/02/24
Abstract |
Background |
Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by vascular remodeling and is associated with endothelial-to-mesenchymal transition (EndoMT). The pigment epithelium-derived factor (PEDF), a secretory protein widely distributed in multiple organs, has been shown to demonstrate anti-EndoMT activity in cardiovascular diseases. In the present study, the role of PEDF in PH was investigated.
Methods |
For PEDF overexpression, Sprague Dawley rats were infected with an adeno-associated virus through injection via the internal jugular vein. To establish PH models, the animals were subjected to monocrotaline or Sugen/hypoxia. Four weeks later, pulmonary artery angiography was performed, and hemodynamic parameters, right ventricular function, and vascular remodeling were evaluated. EndoMT and cell proliferation in the pulmonary arteries were assessed via immunofluorescence staining. Moreover, pulmonary artery endothelial cells (PAECs) isolated from experimental PH rats were cultured to investigate the underlying molecular mechanisms involved.
Results |
PEDF expression was significantly downregulated in PAECs from PH patients and PH model rats. Overexpressed PEDF alleviated the development of PH by improving pulmonary artery morphology and perfusion, reducing pulmonary artery pressure, improving right ventricular function, and alleviating vascular remodeling. PEDF inhibits EndoMT and reduces excessive PAEC proliferation. Moreover, PEDF overexpression reduced EndoMT in cultured PAECs by competitively inhibiting the binding of wnt to LRP6 and downregulating phosphorylation at the 1490 site of LRP6.
Conclusions |
Our findings suggest that PEDF may be a potential therapeutic target for PH. We also found that PEDF can inhibit EndoMT in PAECs and may exert these effects by inhibiting the Wnt/LRP6/β-catenin pathway.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Pigment epithelium-derived factor (PEDF) level was negatively correlated with PH severity. |
• | PEDF overexpression alleviates pulmonary artery pressure. |
• | PEDF overexpression attenuates pulmonary artery remodeling. |
• | PEDF overexpression inhibits endothelial-to-mesenchymal transition (EndoMT) in pulmonary arteries. |
• | PEDF inhibits EndoMT through the wnt/LRP6/β-catenin pathway. |
Keywords : Pigment epithelium-derived factor, Pulmonary hypertension, Vascular remodeling, Endothelial-to-mesenchymal transition
Plan
Vol 172
Article 116303- mars 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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