1. Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension
- Author
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Saadia Eddahibi, Franck Lebrin, Olaf Mercier, Robert Naeije, Mohamed Izikki, Philippe Dartevelle, Benoit Gore, Elie Fadel, Marc Humbert, Gérald Simonneau, and Laurence Dewachter
- Subjects
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 - Abstract
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
- Published
- 2013