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

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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: PMID:25593290   (View Abstract at PubMed)
DOI: DOI:10.1161/CIRCULATIONAHA.114.008750   (Journal Full-text)


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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CDH2HumanPulmonary Arterial Hypertension  IEP mRNA:increased expression:lungRGD 
CTNND1HumanPulmonary Arterial Hypertension  IEP protein:decreased expression:lungRGD 
Cdh2RatPulmonary Arterial Hypertension  ISOCDH2 (Homo sapiens)mRNA:increased expression:lungRGD 
Cdh2MousePulmonary Arterial Hypertension  ISOCDH2 (Homo sapiens)mRNA:increased expression:lungRGD 
Ctnnd1MousePulmonary Arterial Hypertension  ISOCTNND1 (Homo sapiens)protein:decreased expression:lungRGD 
Ctnnd1RatPulmonary Arterial Hypertension  ISOCTNND1 (Homo sapiens)protein:decreased expression:lungRGD 
ITGA5HumanPulmonary Arterial Hypertension  IEP mRNA:increased expression:lungRGD 
Itga5RatPulmonary Arterial Hypertension  ISOITGA5 (Homo sapiens)mRNA:increased expression:lungRGD 
Itga5MousePulmonary Arterial Hypertension  ISOITGA5 (Homo sapiens)mRNA:increased expression:lungRGD 
TGFBR1HumanPulmonary Arterial Hypertension  IEP mRNA:increased expression:lungRGD 
TWIST1HumanPulmonary Arterial Hypertension  IEP mRNA more ...RGD 
Tgfbr1RatPulmonary Arterial Hypertension  ISOTGFBR1 (Homo sapiens)mRNA:increased expression:lungRGD 
Tgfbr1MousePulmonary Arterial Hypertension  ISOTGFBR1 (Homo sapiens)mRNA:increased expression:lungRGD 
Twist1MousePulmonary Arterial Hypertension  ISOTWIST1 (Homo sapiens)mRNA more ...RGD 
Twist1RatPulmonary Arterial Hypertension  ISOTWIST1 (Homo sapiens)mRNA more ...RGD 
VIMHumanPulmonary Arterial Hypertension  IEP protein:increased phosphorylation:lungRGD 
VimRatPulmonary Arterial Hypertension  ISOVIM (Homo sapiens)protein:increased phosphorylation:lungRGD 
VimMousePulmonary Arterial Hypertension  ISOVIM (Homo sapiens)protein:increased phosphorylation:lungRGD 
BMPR2Humanpulmonary hypertension  ISOBmpr2 (Rattus norvegicus)protein:decreased expression:lungRGD 
Bmpr2Ratpulmonary hypertension  IEP protein:decreased expression:lungRGD 
Bmpr2Mousepulmonary hypertension  ISOBmpr2 (Rattus norvegicus)protein:decreased expression:lungRGD 
CDH5Humanpulmonary hypertension  ISOCdh5 (Rattus norvegicus)protein:decreased expression:lungRGD 
CTNND1Humanpulmonary hypertension treatmentISOCtnnd1 (Rattus norvegicus) RGD 
Cdh5Ratpulmonary hypertension  IEP protein:decreased expression:lungRGD 
Cdh5Mousepulmonary hypertension  ISOCdh5 (Rattus norvegicus)protein:decreased expression:lungRGD 
Ctnnd1Ratpulmonary hypertension treatmentIEP  RGD 
Ctnnd1Mousepulmonary hypertension treatmentISOCtnnd1 (Rattus norvegicus) RGD 
TWIST1Humanpulmonary hypertension treatmentISOTwist1 (Rattus norvegicus) RGD 
Twist1Ratpulmonary hypertension treatmentIEP  RGD 
Twist1Mousepulmonary hypertension treatmentISOTwist1 (Rattus norvegicus) RGD 
VIMHumanpulmonary hypertension  ISOVim (Rattus norvegicus)protein:increased expression and increased phosphorylation:lungRGD 
VimRatpulmonary hypertension  IEP protein:increased expression and increased phosphorylation:lungRGD 
VimMousepulmonary hypertension  ISOVim (Rattus norvegicus)protein:increased expression and increased phosphorylation:lungRGD 
CDH5HumanRight Ventricular Hypertrophy  ISOCdh5 (Rattus norvegicus)protein:decreased expression:lungRGD 
CTNND1HumanRight Ventricular Hypertrophy treatmentISOCtnnd1 (Rattus norvegicus) RGD 
Cdh5MouseRight Ventricular Hypertrophy  ISOCdh5 (Rattus norvegicus)protein:decreased expression:lungRGD 
Cdh5RatRight Ventricular Hypertrophy  IEP protein:decreased expression:lungRGD 
Ctnnd1MouseRight Ventricular Hypertrophy treatmentISOCtnnd1 (Rattus norvegicus) RGD 
Ctnnd1RatRight Ventricular Hypertrophy treatmentIEP  RGD 
TWIST1HumanRight Ventricular Hypertrophy treatmentISOTwist1 (Rattus norvegicus) RGD 
Twist1MouseRight Ventricular Hypertrophy treatmentISOTwist1 (Rattus norvegicus) RGD 
Twist1RatRight Ventricular Hypertrophy treatmentIEP  RGD 
BMPR2HumanVascular Remodeling  ISOBmpr2 (Rattus norvegicus) RGD 
Bmpr2MouseVascular Remodeling  ISOBmpr2 (Rattus norvegicus) RGD 
Bmpr2RatVascular Remodeling  IMP  RGD 
Bmpr2em1AngRatVascular Remodeling  IMP  RGD 
SD-Bmpr2em1Ang+/-RatVascular Remodeling  IMP  RGD 
TWIST1HumanVascular Remodeling  ISOTwist1 (Rattus norvegicus)protein:increased expression:lungRGD 
Twist1MouseVascular Remodeling  ISOTwist1 (Rattus norvegicus)protein:increased expression:lungRGD 
Twist1RatVascular Remodeling  IEP protein:increased expression:lungRGD 
VIMHumanVascular Remodeling  ISOVim (Rattus norvegicus)protein:increased phosphorylation:lungRGD 
VimRatVascular Remodeling  IEP protein:increased phosphorylation:lungRGD 
VimMouseVascular Remodeling  ISOVim (Rattus norvegicus)protein:increased phosphorylation:lungRGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Bmpr2Ratvascular smooth muscle hypertrophy  IMP  RGD 
Bmpr2em1AngRatvascular smooth muscle hypertrophy  IMP  RGD 
SD-Bmpr2em1Ang+/-Ratvascular smooth muscle hypertrophy  IMP  RGD 
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 2)
Cdh2  (cadherin 2)
Cdh5  (cadherin 5)
Ctnnd1  (catenin 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