RGD Reference Report - Endothelial-to-mesenchymal transition in pulmonary hypertension. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Endothelial-to-mesenchymal transition in pulmonary hypertension.

Authors: Ranchoux, Benoît  Antigny, Fabrice  Rucker-Martin, Catherine  Hautefort, Aurélie  Péchoux, Christine  Bogaard, Harm Jan  Dorfmüller, Peter  Remy, Séverine  Lecerf, Florence  Planté, Sylvie  Chat, Sophie  Fadel, Elie  Houssaini, Amal  Anegon, Ignacio  Adnot, Serge  Simonneau, Gerald  Humbert, Marc  Cohen-Kaminsky, Sylvia  Perros, Frédéric 
Citation: Ranchoux B, etal., Circulation. 2015 Mar 17;131(11):1006-18. doi: 10.1161/CIRCULATIONAHA.114.008750. Epub 2015 Jan 15.
RGD ID: 38500244
Pubmed: (View Article at PubMed) PMID:25593290
DOI: Full-text: DOI:10.1161/CIRCULATIONAHA.114.008750


BACKGROUND: The vascular remodeling responsible for pulmonary arterial hypertension (PAH) involves predominantly the accumulation of α-smooth muscle actin-expressing mesenchymal-like cells in obstructive pulmonary vascular lesions. Endothelial-to-mesenchymal transition (EndoMT) may be a source of those α-smooth muscle actin-expressing cells.
METHODS AND RESULTS: In situ evidence of EndoMT in human PAH was obtained by using confocal microscopy of multiple fluorescent stainings at the arterial level, and by using transmission electron microscopy and correlative light and electron microscopy at the ultrastructural level. Findings were confirmed by in vitro analyses of human PAH and control cultured pulmonary artery endothelial cells. In addition, the mRNA and protein signature of EndoMT was recognized at the arterial and lung level by quantitative real-time polymerase chain reaction and Western blot analyses. We confirmed our human observations in established animal models of pulmonary hypertension (monocrotaline and SuHx). After establishing the first genetically modified rat model linked to BMPR2 mutations (BMPR2(Δ140Ex1/+) rats), we demonstrated that EndoMT is linked to alterations in signaling of BMPR2, a gene that is mutated in 70% of cases of familial PAH and in 10% to 40% of cases of idiopathic PAH. We identified molecular actors of this pathological transition, including twist overexpression and vimentin phosphorylation. We demonstrated that rapamycin partially reversed the protein expression patterns of EndoMT, improved experimental PAH, and decreased the migration of human pulmonary artery endothelial cells, providing the proof of concept that EndoMT is druggable.
CONCLUSIONS: EndoMT is linked to alterations in BPMR2 signaling and is involved in the occlusive vas cular remodeling of PAH, findings that may have therapeutic implications.

Annotation

Disease Annotations    

Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Bmpr2  (bone morphogenetic protein receptor type 2)
Bmpr2em1Ang  (bone morphogenetic protein receptor type 2; ZFN induced mutant 1, Ang)
Cdh2  (cadherin 2)
Cdh5  (cadherin 5)
Ctnnd1  (catenin delta 1)
Itga5  (integrin subunit alpha 5)
Tgfbr1  (transforming growth factor, beta receptor 1)
Twist1  (twist family bHLH transcription factor 1)
Vim  (vimentin)

Genes (Mus musculus)
Bmpr2  (bone morphogenetic protein receptor, type II (serine/threonine kinase))
Cdh2  (cadherin 2)
Cdh5  (cadherin 5)
Ctnnd1  (catenin (cadherin associated protein), delta 1)
Itga5  (integrin alpha 5 (fibronectin receptor alpha))
Tgfbr1  (transforming growth factor, beta receptor I)
Twist1  (twist basic helix-loop-helix transcription factor 1)
Vim  (vimentin)

Genes (Homo sapiens)
BMPR2  (bone morphogenetic protein receptor type 2)
CDH2  (cadherin 2)
CDH5  (cadherin 5)
CTNND1  (catenin delta 1)
ITGA5  (integrin subunit alpha 5)
TGFBR1  (transforming growth factor beta receptor 1)
TWIST1  (twist family bHLH transcription factor 1)
VIM  (vimentin)

Strains
SD-Bmpr2em1Ang+/-  (NA)


Additional Information