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Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension.

Gore B, Izikki M, Mercier O, Dewachter L, Fadel E, Humbert M, Dartevelle P, Simonneau G, Naeije R, Lebrin F, Eddahibi S - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U999, Le Plessis-Robinson, France.

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.

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Mouse right ventricular (RV) systolic pressure (RVSP, mm Hg) (A). (B) RV hypertrophy reflected by the RV/(left ventricle+septum) weight ratio. (C) Percentage of lung vessel thickness. (D) Percentages of nonmuscularized (NM), partially muscularized (PM), and fully muscularized (M) lung vessels (top panel). Representative images for muscularization of distal pulmonary arteries (bottom panel). Values are mean±SEM. *P<0.05 and **P<0.01 compared with wild-type mice under the same conditions.
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pone-0100310-g004: Mouse right ventricular (RV) systolic pressure (RVSP, mm Hg) (A). (B) RV hypertrophy reflected by the RV/(left ventricle+septum) weight ratio. (C) Percentage of lung vessel thickness. (D) Percentages of nonmuscularized (NM), partially muscularized (PM), and fully muscularized (M) lung vessels (top panel). Representative images for muscularization of distal pulmonary arteries (bottom panel). Values are mean±SEM. *P<0.05 and **P<0.01 compared with wild-type mice under the same conditions.

Mentions: In normoxia, RVSP, RV/LV+S, and distal-artery muscularization were not significantly different between Eng+/− and wild-type mice (Figures 3A, B and C). After 3 weeks of chronic hypoxia, the increases in RVSP, RV/LV+S, and distal pulmonary artery muscularization were smaller in the Eng+/− mice than in the wild-type mice (Figure 4) (P<0.05).


Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension.

Gore B, Izikki M, Mercier O, Dewachter L, Fadel E, Humbert M, Dartevelle P, Simonneau G, Naeije R, Lebrin F, Eddahibi S - PLoS ONE (2014)

Mouse right ventricular (RV) systolic pressure (RVSP, mm Hg) (A). (B) RV hypertrophy reflected by the RV/(left ventricle+septum) weight ratio. (C) Percentage of lung vessel thickness. (D) Percentages of nonmuscularized (NM), partially muscularized (PM), and fully muscularized (M) lung vessels (top panel). Representative images for muscularization of distal pulmonary arteries (bottom panel). Values are mean±SEM. *P<0.05 and **P<0.01 compared with wild-type mice under the same conditions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4067299&req=5

pone-0100310-g004: Mouse right ventricular (RV) systolic pressure (RVSP, mm Hg) (A). (B) RV hypertrophy reflected by the RV/(left ventricle+septum) weight ratio. (C) Percentage of lung vessel thickness. (D) Percentages of nonmuscularized (NM), partially muscularized (PM), and fully muscularized (M) lung vessels (top panel). Representative images for muscularization of distal pulmonary arteries (bottom panel). Values are mean±SEM. *P<0.05 and **P<0.01 compared with wild-type mice under the same conditions.
Mentions: In normoxia, RVSP, RV/LV+S, and distal-artery muscularization were not significantly different between Eng+/− and wild-type mice (Figures 3A, B and C). After 3 weeks of chronic hypoxia, the increases in RVSP, RV/LV+S, and distal pulmonary artery muscularization were smaller in the Eng+/− mice than in the wild-type mice (Figure 4) (P<0.05).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U999, Le Plessis-Robinson, France.

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.

Show MeSH
Related in: MedlinePlus