Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndrome
Background & Aims: Hepatopulmonary syndrome (HPS) results from portal hypertension, with or without cirrhosis, and is marked by pulmonary vascular dilations leading to severe hypoxemia. Although placental growth factor (PlGF) is important for vascular growth and endothelial function, its rol...
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2025-03-01
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| author | Fabien Robert Feriel Benchenouf My Ngoc Ha Alessandra Cuomo Mina Ottaviani Maxime Surbier Raphaël Thuillet Corinne Normand Florent Dumont Céline Verstuyft Frederic Fiore Frederic Guinut Marc Humbert Audrey Coilly Emmanuel Gonzales Olivier Sitbon Ly Tu Christophe Guignabert Laurent Savale |
| author_facet | Fabien Robert Feriel Benchenouf My Ngoc Ha Alessandra Cuomo Mina Ottaviani Maxime Surbier Raphaël Thuillet Corinne Normand Florent Dumont Céline Verstuyft Frederic Fiore Frederic Guinut Marc Humbert Audrey Coilly Emmanuel Gonzales Olivier Sitbon Ly Tu Christophe Guignabert Laurent Savale |
| author_sort | Fabien Robert |
| collection | DOAJ |
| description | Background & Aims: Hepatopulmonary syndrome (HPS) results from portal hypertension, with or without cirrhosis, and is marked by pulmonary vascular dilations leading to severe hypoxemia. Although placental growth factor (PlGF) is important for vascular growth and endothelial function, its role in HPS is unclear. This study investigated the involvement of PlGF in experimental models of HPS and in patients. Methods: Circulating PlGF levels were measured in 64 controls and 137 patients with liver disease, with or without HPS. Two rat models, common bile duct ligation (CBDL) and long-term partial portal vein ligation (PPVL), were used. Plgf-knockout (Plgf–/–) rats were generated using CRISPR-Cas9. Lung RNA-sequencing analysis was performed in the CBDL model. The effects of PlGF on endothelial nitric oxide synthase (eNOS) activity in human pulmonary microvascular endothelial cells were also investigated. Results: Circulating PlGF levels were significantly higher in patients with cirrhosis compared with healthy controls (29.4 ± 1.2 vs. 20.2 ± 0.8 pg/ml, p <0.0001), but no difference were found between patients with and without HPS. PlGF levels were not elevated in patients with extrahepatic portal hypertension. In Plgf–/– rats, there was a protective effect against CBDL-induced HPS, whereas PPVL-induced HPS severity remained unchanged. RNA sequencing coupled with ingenuity pathway analysis identified significant interactions between PlGF and pulmonary eNOS activity. Following CBDL, Plgf–/– rats showed decreased pulmonary eNOS activity and reduced circulating nitric oxide metabolites. In vitro, PlGF stimulation enhanced eNOS activity in human pulmonary microvascular endothelial cells, whereas PlGF knockdown led to a decrease. Conclusions: These findings indicate that PlGF aggravates cirrhosis-induced HPS through modulation of pulmonary eNOS activity, and is not involved in HPS from extrahepatic portal hypertension. Impact and implications:: This study identified PlGF as a significant contributor to the exacerbation of HPS associated with cirrhosis, through its regulation of pulmonary nitric oxide production. Our findings demonstrated that PlGF deficiency mitigates the severity of both cirrhosis and HPS in the CBDL model, highlighting its potential as a therapeutic target in cirrhosis-induced HPS. Notably, this protective effect was absent in the PPVL model, which induces HPS associated with portal hypertension without cirrhosis. These results open avenues for novel pharmacological interventions aiming to improve outcomes for patients with cirrhosis-induced HPS. |
| format | Article |
| id | doaj-art-3900c7e3ce8e41adba30c2e9a3ab02d9 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| spelling | doaj-art-3900c7e3ce8e41adba30c2e9a3ab02d92025-02-03T04:16:52ZengElsevierJHEP Reports2589-55592025-03-0173101297Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndromeFabien Robert0Feriel Benchenouf1My Ngoc Ha2Alessandra Cuomo3Mina Ottaviani4Maxime Surbier5Raphaël Thuillet6Corinne Normand7Florent Dumont8Céline Verstuyft9Frederic Fiore10Frederic Guinut11Marc Humbert12Audrey Coilly13Emmanuel Gonzales14Olivier Sitbon15Ly Tu16Christophe Guignabert17Laurent Savale18Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; Department of Translational Medical Sciences, Federico II University, Naples, ItalyUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Centre de Ressource Biologique Paris-Saclay, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Bicêtre, Le Kremlin Bicêtre, FranceCentre d'Immunophénomique (CIPHE), Aix Marseille Université, INSERM, CNRS, CELPHEDIA, PHENOMIN, Marseille, FranceJanvier-Labs, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de L’hypertension Pulmonaire (PulmoTension), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, FranceCentre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Villejuif, France; INSERM UMR_S 1193, Hepatinov, University Paris-Saclay, Orsay, FranceINSERM UMR_S 1193, Hepatinov, University Paris-Saclay, Orsay, France; Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Biliary Atresia and Genetic Cholestasis, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de L’hypertension Pulmonaire (PulmoTension), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France; Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de L’hypertension Pulmonaire (PulmoTension), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Corresponding author. Address: INSERM UMR_S 999, Team 1, Faculté de Médecine, Université Paris-Saclay, Bâtiment de recherche (2e étage), 63 rue Gabriel Péri, 94276 Le Kremlin Bicêtre, France. Tel: +33 1 40 94 88 33.Background & Aims: Hepatopulmonary syndrome (HPS) results from portal hypertension, with or without cirrhosis, and is marked by pulmonary vascular dilations leading to severe hypoxemia. Although placental growth factor (PlGF) is important for vascular growth and endothelial function, its role in HPS is unclear. This study investigated the involvement of PlGF in experimental models of HPS and in patients. Methods: Circulating PlGF levels were measured in 64 controls and 137 patients with liver disease, with or without HPS. Two rat models, common bile duct ligation (CBDL) and long-term partial portal vein ligation (PPVL), were used. Plgf-knockout (Plgf–/–) rats were generated using CRISPR-Cas9. Lung RNA-sequencing analysis was performed in the CBDL model. The effects of PlGF on endothelial nitric oxide synthase (eNOS) activity in human pulmonary microvascular endothelial cells were also investigated. Results: Circulating PlGF levels were significantly higher in patients with cirrhosis compared with healthy controls (29.4 ± 1.2 vs. 20.2 ± 0.8 pg/ml, p <0.0001), but no difference were found between patients with and without HPS. PlGF levels were not elevated in patients with extrahepatic portal hypertension. In Plgf–/– rats, there was a protective effect against CBDL-induced HPS, whereas PPVL-induced HPS severity remained unchanged. RNA sequencing coupled with ingenuity pathway analysis identified significant interactions between PlGF and pulmonary eNOS activity. Following CBDL, Plgf–/– rats showed decreased pulmonary eNOS activity and reduced circulating nitric oxide metabolites. In vitro, PlGF stimulation enhanced eNOS activity in human pulmonary microvascular endothelial cells, whereas PlGF knockdown led to a decrease. Conclusions: These findings indicate that PlGF aggravates cirrhosis-induced HPS through modulation of pulmonary eNOS activity, and is not involved in HPS from extrahepatic portal hypertension. Impact and implications:: This study identified PlGF as a significant contributor to the exacerbation of HPS associated with cirrhosis, through its regulation of pulmonary nitric oxide production. Our findings demonstrated that PlGF deficiency mitigates the severity of both cirrhosis and HPS in the CBDL model, highlighting its potential as a therapeutic target in cirrhosis-induced HPS. Notably, this protective effect was absent in the PPVL model, which induces HPS associated with portal hypertension without cirrhosis. These results open avenues for novel pharmacological interventions aiming to improve outcomes for patients with cirrhosis-induced HPS.http://www.sciencedirect.com/science/article/pii/S258955592400301XLiver cirrhosisPortal hypertensionPulmonary endothelial dysfunctionPartial portal vein ligationCommon bile duct ligationIntrapulmonary vascular dilations |
| spellingShingle | Fabien Robert Feriel Benchenouf My Ngoc Ha Alessandra Cuomo Mina Ottaviani Maxime Surbier Raphaël Thuillet Corinne Normand Florent Dumont Céline Verstuyft Frederic Fiore Frederic Guinut Marc Humbert Audrey Coilly Emmanuel Gonzales Olivier Sitbon Ly Tu Christophe Guignabert Laurent Savale Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndrome JHEP Reports Liver cirrhosis Portal hypertension Pulmonary endothelial dysfunction Partial portal vein ligation Common bile duct ligation Intrapulmonary vascular dilations |
| title | Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndrome |
| title_full | Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndrome |
| title_fullStr | Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndrome |
| title_full_unstemmed | Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndrome |
| title_short | Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndrome |
| title_sort | placental growth factor modulates endothelial no production and exacerbates experimental hepatopulmonary syndrome |
| topic | Liver cirrhosis Portal hypertension Pulmonary endothelial dysfunction Partial portal vein ligation Common bile duct ligation Intrapulmonary vascular dilations |
| url | http://www.sciencedirect.com/science/article/pii/S258955592400301X |
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