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.

Inhibin B suppresses anoikis resistance and migration through the transforming growth factor‐β signaling pathway in nasopharyngeal carcinoma

“…We have data suggesting that INHBB expression is positively correlated with that of ALK1 and TGF‐βR2 (unpublished data, 2009). In endothelial cells, TGF‐β activated ALK1, which transmits signals through the ALK1/Smad1/5 pathways and, to a lesser degree, the Smad2/3 signaling pathways, stimulated endothelial cell proliferation and migration . Thus, we have reason to believe that INHBB can induce the anoikis‐resistant cell EMT modification through the TGF‐β/Smads pathway to affect tumor growth, invasion, and metastasis (Figure ).…”

“…pathways and, to a lesser degree, the Smad2/3 signaling pathways, stimulated endothelial cell proliferation and migration. [43][44][45] Thus, we have reason to believe that INHBB can induce the anoikis-resistant cell EMT modification through the TGF-β/Smads pathway to affect tumor growth, invasion, and metastasis ( Figure 6).…”

Differential expression of microRNA in the lungs of rats with pulmonary arterial hypertension

“…TGF-β has been reported to contribute to PAH development, as endothelial TGF-β/activin receptor-like kinase 1/endoglin signaling leads to pulmonary blood vessel angiogenesis, macrophage infiltration, and cytokine expression in the lungs (23,24). The present study identified miR-148-3p in PAH, and identified TGF-β as a potential target of miR-148-3p.…”

miR‐142‐3p Is a Regulator of the TGFβ‐Mediated Vascular Smooth Muscle Cell Phenotype

“…While PAH can be induced by the overexpression of IL‐6 and TNFα, BMP signaling inhibits the TNFα‐induced activation of NF‐κB by promoting an MRTF‐A/NF‐κB inhibitory complex, thereby preventing inflammation in PASMCs [Wang et al, ]. Interestingly, mutations in members of the TGFβ superfamily of receptors, such as endoglin and the activin‐like receptor 1 (ALK‐1), have also been observed in PAH [Gore et al, ]. Therefore, further investigation remains necessary to determine whether TGFβ‐induced miR‐142‐3p plays an anti‐inflammatory role in VSMCs by targeting pro‐inflammatory cytokines such as IL‐6.…”