Evidence map›Paper›PMID 27045138›Full record

ArticleCirculation2016

In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug.

Rachel K Hopper, Jan-Renier A J Moonen, Isabel Diebold, Aiqin Cao, Christopher J Rhodes, Nancy F Tojais, Jan K Hennigs, Mingxia Gu, Lingli Wang, Marlene Rabinovitch

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 148 papers.

0numbers the graph read from it
0cells of the map it votes in
148citing papers in PubMed
19.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

148 citing papers in PubMed, 232 citations in OpenAlex.

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  12. Signaling pathways and targeted therapy for pulmonary hypertension.Signal transduction and targeted therapy · 2025
    Review
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88 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 2 institutions in 1 country.

Rachel K HopperFrom Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
Jan-Renier A J MoonenFrom Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
Isabel DieboldFrom Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
Aiqin CaoFrom Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
Christopher J RhodesFrom Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
Nancy F TojaisFrom Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
Jan K HennigsFrom Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
Mingxia GuFrom Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
Lingli WangFrom Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
Marlene RabinovitchFrom Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.). marlener@stanford.edu.
Children's Hospital of Philadelphia · USUniversity of Pennsylvania · US

Funding

MICHIGAN INSTITUTE FOR CLINICAL AND HEALTH RESEARCH (MICHR) (UL1): (BPCA)UL1RR024986 · NCRR · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHANLEY, THOMAS P. · 2007 to 2011
$51.2M
Michigan Institute for Clinical and Health Research (MCHR)UL1TR000433 · NCATS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI MASHOUR, GEORGE ALEXANDER · 2012 to 2016
$49.9M
Spectrum Stanford Center for clinical and Translational Research and EducationUL1TR001085 · NCATS · STANFORD UNIVERSITY · PI CULLEN, MARK RICHARD, GREENBERG, HARRY BERNARD · 2013 to 2017
$37.1M
Stanford Center for Clinical and Translational Education and Research (SCCTER)UL1UL1RR025744 · NCRR · STANFORD UNIVERSITY · PI GREENBERG, HARRY BERNARD · 2008 to 2011
$22.4M
Pulmonary Hypertension in Genetically Modified MiceR01HL074186 · NHLBI · STANFORD UNIVERSITY · PI RABINOVITCH, MARLENE · 2004 to 2022
$10.4M
Pulmonary Hypertension Breakthrough InitiativeR24HL123767 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI ALDRED, MICHEALA A, ERZURUM, SERPIL C. · 2014 to 2017
$10.1M
iPSC Derived EC as Surrogates Using Pulmonary Hypertension as a Prototype DiseaseU01HL107393 · NHLBI · STANFORD UNIVERSITY · PI RABINOVITCH, MARLENE, SNYDER, MICHAEL P. · 2011 to 2015
$8.7M
The BMP-PPARy Axis and Pulmonary HypertensionR01HL087118 · NHLBI · STANFORD UNIVERSITY · PI RABINOVITCH, MARLENE · 2008 to 2022
$7.2M
Airway redox biochemistry as a deteriminant of asthma phenotype during adolescen*U10HL109250 · NHLBI · UNIVERSITY OF VIRGINIA · PI ERZURUM, SERPIL C., GASTON, BENJAMIN · 2011 to 2016
$4.2M
Integrative Omics as a Discovery Tool for Pulmonary HypertensionR01HL122887 · NHLBI · STANFORD UNIVERSITY · PI NICOLLS, MARK ROBERT, RABINOVITCH, MARLENE · 2015 to 2018
$4.1M
NCATS NIH HHS UL1 TR000433NCATS NIH HHS UL1 TR001085NCRR NIH HHS UL1 RR024986NCRR NIH HHS UL1 RR025744NHLBI NIH HHS R01 HL074186NHLBI NIH HHS R01 HL087118NHLBI NIH HHS R01 HL122887NHLBI NIH HHS R24 HL123767NHLBI NIH HHS U01 HL107393NHLBI NIH HHS U10 HL109250
6 · The paper itself

Abstract

backgroundWe previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial endothelial cells (PAECs) from patients who had idiopathic pulmonary arterial hypertension (PAH) in comparison with controls. Because HMGA1 promotes epithelial-to-mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)-like mesenchymal phenotype (endothelial-to-mesenchymal transition), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced idiopathic PAH. METHODS AND

resultsWe documented increased HMGA1 in PAECs cultured from idiopathic PAH versus donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to pulmonary arterial endothelium, and identified many cells double-positive for HMGA1 and SM22α in occlusive and plexogenic lesions. Because decreased expression and function of bone morphogenetic protein receptor 2 (BMPR2) is observed in PAH, we reduced BMPR2 by small interfering RNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced platelet endothelial cell adhesion molecule 1 (CD31) and increased endothelial-to-mesenchymal transition markers, αSM actin, SM22α, calponin, phospho-vimentin, and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSM actin was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary endothelial cells from mice with endothelial cell-specific loss of Bmpr2 showed similar gene and protein changes.

conclusionsIncreased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.

Indexed as

AdolescentAdultAnimalsBone Morphogenetic Protein Receptors, Type IICells, CulturedChildEndothelium, VascularEpithelial-Mesenchymal TransitionFemaleHMGA1a ProteinHumansHypertension, PulmonaryInfantMaleMiceMice, TransgenicBMPR2 protein, humanBone Morphogenetic Protein Receptors, Type IIHMGA1a ProteinSNAI1 protein, humanSnail Family Transcription Factorsendothelial-to-mesenchymal transitionHMGA1 proteinhypertension, pulmonary

Identifiers

PMID27045138
PMCPMC4856565
OpenAlexW2341828371

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.