Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

Ranchoux, Benoît; Tanguay, Virginie F.; Perros, Frédèric

doi:10.1007/978-981-15-1185-1_6

Cited by 71 publications

(126 citation statements)

References 34 publications

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“…(31) Both endothelial dysfunction and, in particular, EndMT have been demonstrated to contribute such adult pathologies. (32,33) Therefore, we anticipate that ECFCs may be interesting to investigate these secondary conditions in FOP. In addition, more frequent and larger blood vessels were recently found in lesions from FOP donors compared with nongenetic forms of HO.…”

Section: Discussionmentioning

confidence: 99%

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Sánchez‐Duffhues

Williams

Benderitter³

et al. 2019

JBMR Plus

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Fibrodysplasia ossificans progressiva (FOP) is an extremely rare congenital form of heterotopic ossification (HO), caused by heterozygous mutations in the activin A type I receptor (ACVR1), that encodes the bone morphogenetic protein (BMP) type I receptor ALK2. These mutations enable ALK2 to induce downstream signaling in response to activins, thereby turning them into bone‐inducing agents. To date, there is no cure for FOP. The further development of FOP patient‐derived models may contribute to the discovery of novel biomarkers and therapeutic approaches. Nevertheless, this has traditionally been a challenge, as biopsy sampling often triggers HO. We have characterized peripheral blood‐derived endothelial colony‐forming cells (ECFCs) from three independent FOP donors as a new model for FOP. FOP ECFCs are prone to undergo endothelial‐to‐mesenchymal transition and exhibit increased ALK2 downstream signaling and subsequent osteogenic differentiation upon stimulation with activin A. Moreover, we have identified a new class of small molecule macrocycles with potential activity against ALK2 kinase. Finally, using FOP ECFCs, we have selected OD36 and OD52 as potent inhibitors with excellent kinase selectivity profiles that potently antagonize mutant ALK2 signaling and osteogenic differentiation. We expect that these results will contribute to the development of novel ALK2 clinical candidates for the treatment of FOP. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Sánchez‐Duffhues

Williams

Benderitter³

et al. 2019

JBMR Plus

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“…In PAH and rat Sugen/hypoxia model, EndoMT was estimated to occur in 5% of vessels, based on co-expression of SMC and endothelial markers [37]. Similarly, co-localization of VE-cadherin and CD31 with αSMA was reported in intimal and plexiform lesions [38]. In contrast, another study investigating cell type marker localization and expression in human plexiform lesions and adjacent PAs found no evidence of co-expression of SMC and EC markers in either plexiform or concentric lesions [30].…”

Section: Discussionmentioning

confidence: 99%

Resident cell lineages are preserved in pulmonary vascular remodeling

Crnković

Marsh

Agha

et al. 2018

The Journal of Pathology

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Pulmonary vascular remodeling is the main pathological hallmark of pulmonary hypertension disease. We undertook a comprehensive and multilevel approach to investigate the origin of smooth muscle actin‐expressing cells in remodeled vessels. Transgenic mice that allow for specific, inducible, and permanent labeling of endothelial (Cdh5‐tdTomato), smooth muscle (Acta2‐, Myh11‐tdTomato), pericyte (Cspg4‐tdTomato), and fibroblast (Pdgfra‐tdTomato) lineages were used to delineate the cellular origins of pulmonary vascular remodeling. Mapping the fate of major lung resident cell types revealed smooth muscle cells (SMCs) as the predominant source of cells that populate remodeled pulmonary vessels in chronic hypoxia and allergen‐induced murine models. Combining in vivo cell type‐specific, time‐controlled labeling of proliferating cells with a pulmonary artery phenotypic explant assay, we identified proliferation of SMCs as an underlying remodeling pathomechanism. Multicolor immunofluorescence analysis showed a preserved pattern of cell type marker localization in murine and human pulmonary arteries, in both donors and idiopathic pulmonary arterial hypertension (IPAH) patients. Whilst neural glial antigen 2 (chondroitin sulfate proteoglycan 4) labeled mostly vascular supportive cells with partial overlap with SMC markers, PDGFRα‐expressing cells were observed in the perivascular compartment. The luminal vessel side was lined by a single cell layer expressing endothelial markers followed by an adjacent and distinct layer defined by SMC marker expression and pronounced thickening in remodeled vessels. Quantitative flow cytometric analysis of single cell digests of diverse pulmonary artery layers showed the preserved separation into two discrete cell populations expressing either endothelial cell (EC) or SMC markers in human remodeled vessels. Additionally, we found no evidence of overlap between EC and SMC ultrastructural characteristics using electron microscopy in either donor or IPAH arteries. Lineage‐specific marker expression profiles are retained during pulmonary vascular remodeling without any indication of cell type conversion. The expansion of resident SMCs is the major underlying and evolutionarily conserved paradigm of pulmonary vascular disease pathogenesis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Vascular endothelial cells acquire a mesenchymal phenotype following exposure to several cytokines and growth factors, including transforming growth factor β (TGF-β), PDGF, and FGF which are induced by shear stress, hypoxia, and inflammation (10). EndMT-modified endothelial cells acquire additional characteristics of mesenchymal cells, and recent reports have indicated a critical role of EndMT in the development of PAH-specific neointimal lesions in PAs (11–13). Although both medial wall thickness and neointimal lesions in PAs are common pathological findings in PAH, a greater contribution of neointimal lesions in the elevation of pulmonary arterial pressure was reported in experimental PAH (14), suggesting an important involvement of EndMT.…”

Section: Introductionmentioning

confidence: 99%

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Tsutsumi

Nagaoka

Yoshida

et al. 2019

Preprint

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Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. The inhibitory effects of nintedanib were evaluated both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and pulmonary hemodynamics and PAs pathology were evaluated. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented both in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.

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Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

Cited by 71 publications

References 34 publications

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Resident cell lineages are preserved in pulmonary vascular remodeling

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

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