Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension
| Autor: | Saadia Eddahibi, Franck Lebrin, Olaf Mercier, Robert Naeije, Mohamed Izikki, Philippe Dartevelle, Benoit Gore, Elie Fadel, Marc Humbert, Gérald Simonneau, Laurence Dewachter |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Physiology medicine.medical_treatment Activin Receptors Type II Respiratory System lcsh:Medicine Pathogenesis Immunoenzyme Techniques Mice Physiologie générale Transforming Growth Factor beta Molecular Cell Biology Familial Primary Pulmonary Hypertension Phosphorylation lcsh:Science Cells Cultured Mice Knockout Multidisciplinary biology Chemistry Reverse Transcriptase Polymerase Chain Reaction Endoglin Intracellular Signaling Peptides and Proteins Prognosis medicine.anatomical_structure Cell Processes Female Anatomy Signal Transduction Research Article medicine.medical_specialty Cell Physiology Endothelium Hypertension Pulmonary Blotting Western Enzyme-Linked Immunosorbent Assay Pulmonary Artery Real-Time Polymerase Chain Reaction Cell Growth Proinflammatory cytokine Internal medicine medicine Animals Humans RNA Messenger Cell Proliferation Growth factor lcsh:R Biology and Life Sciences Transforming growth factor beta Cell Biology medicine.disease Pulmonary hypertension Mice Inbred C57BL Endocrinology Case-Control Studies biology.protein Cardiovascular Anatomy lcsh:Q Endothelium Vascular Physiological Processes Receptors Transforming Growth Factor beta Transforming growth factor Follow-Up Studies |
| Zdroj: | PLoS ONE PloS one, 9 (6 PLoS ONE, Vol 9, Iss 6, p e100310 (2014) |
| ISSN: | 1932-6203 |
| Popis: | Mutations affecting transforming growth factor-beta (TGF-β) superfamily receptors, activin receptor-like kinase (ALK)-1, and endoglin (ENG) occur in patients with pulmonary arterial hypertension (PAH). To determine whether the TGF-β/ALK1/ENG pathway was involved in PAH, we investigated pulmonary TGF-β, ALK1, ALK5, and ENG expressions in human lung tissue and cultured pulmonary-artery smooth-muscle-cells (PA-SMCs) and pulmonary endothelial cells (PECs) from 14 patients with idiopathic PAH (iPAH) and 15 controls. Seeing that ENG was highly expressed in PEC, we assessed the effects of TGF-β on Smad1/5/8 and Smad2/3 activation and on growth factor production by the cells. Finally, we studied the consequence of ENG deficiency on the chronic hypoxic-PH development by measuring right ventricular (RV) systolic pressure (RVSP), RV hypertrophy, and pulmonary arteriolar remodeling in ENG-deficient (Eng+/-) and wild-type (Eng+/+) mice. We also evaluated the pulmonary blood vessel density, macrophage infiltration, and cytokine expression in the lungs of the animals. Compared to controls, iPAH patients had higher serum and pulmonary TGF-β levels and increased ALK1 and ENG expressions in lung tissue, predominantly in PECs. Incubation of the cells with TGF-β led to Smad1/5/8 phosphorylation and to a production of FGF2, PDGFb and endothelin-inducing PA-SMC growth. Endoglin deficiency protected mice from hypoxic PH. As compared to wild-type, Eng+/- mice had a lower pulmonary vessel density, and no change in macrophage infiltration after exposure to chronic hypoxia despite the higher pulmonary expressions of interleukin-6 and monocyte chemoattractant protein-1. The TGF-β/ALK1/ENG signaling pathway plays a key role in iPAH and experimental hypoxic PH via a direct effect on PECs leading to production of growth factors and inflammatory cytokines involved in the pathogenesis of PAH. Journal Article Research Support, Non-U.S. Gov't SCOPUS: ar.j info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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