title: Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension.
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.
authors: INSERM U999, Le Plessis-Robinson, France.
authors: Benoît
authors: B
authors: Gore
authors: INSERM U999, Le Plessis-Robinson, France.
authors: Mohamed
authors: M
authors: Izikki
authors: Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Olaf
authors: O
authors: Mercier
authors: Laboratory of Physiology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium.
authors: Laurence
authors: L
authors: Dewachter
authors: Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Elie
authors: E
authors: Fadel
authors: INSERM U999, Le Plessis-Robinson, France.
authors: Marc
authors: M
authors: Humbert
authors: Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Philippe
authors: P
authors: Dartevelle
authors: INSERM U999, Le Plessis-Robinson, France.
authors: Gerald
authors: G
authors: Simonneau
authors: Laboratory of Physiology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium.
authors: Robert
authors: R
authors: Naeije
authors: INSERM U833, Collège de France, Paris, France.
authors: Franck
authors: F
authors: Lebrin
authors: INSERM U999, Le Plessis-Robinson, France; Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Saadia
authors: S
authors: Eddahibi
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011379:Prognosis; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II