CoChat
Sign Up
Cited by 76Signaling Pathways in DiseaseCongenital heart defects researchDevelopmental Biology and Gene Regulation

VEGF and RANKL Regulation of NFATc1 in Heart Valve Development

Open access
Combs, Michelle D., Yutzey, Katherine E.·2009·Circulation Research
DOI 10.1161/circresaha.109.196469PMC PMC2749238
Open this paper in CoChat — free accountOpen PDF

Abstract

Rationale: NFATc1 (nuclear factor of activated T-cells cytoplasmic 1) activity in endocardial cushion (ECC) endothelial cells is required for normal ECC growth and extracellular matrix (ECM) remodeling during heart valve development. Objective: The mechanisms of NFATc1 activation and downstream effects on cell proliferation and ECM-remodeling enzyme gene expression were examined in NFATc1 mutant mice and chick ECC explants. Methods and Results: NFATc1 −/− mice display reduced proliferation of ECC endothelial and mesenchymal cells at embryonic day 10.5, whereas myocardial cells are unaffected. Vascular endothelial growth factor A (VEGF) activates NFATc1 and promotes ECC cell proliferation via the regulatory phosphatase, calcineurin, and mitogen-activated protein kinase–extracellular signal-regulated kinase 1–extracellular signal-regulated kinase 1/2 (MEK1-ERK1/2)–dependent signaling. As ECCs mature, RANKL (receptor activator of nuclear factor κB ligand) and the ECM-remodeling enzyme cathepsin K (CtsK) are expressed by ECC endothelial cells. RANKL inhibits VEGF-induced cell proliferation while causing increased expression of CtsK via calcineurin/NFATc1 and c-Jun N-terminal kinase (JNK)1/2-dependent signaling. Conclusion: These data support a novel mechanism for the transition from ECC growth to remodeling in which NFATc1 promotes a sequential pattern of gene expression via cooperation with ligand-specific cofactors such as MEK1-ERK1/2 or JNK1/2.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1161/circresaha.109.196469

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • NicheNet analysis identifies activation of signalling pathways classically associated with EndMT initiation and mesenchymal development, including TGFβ superfamily, WNT, VEGF, and FGF signalling, signalling toward endocardial cells at E10.5.

    “In our analysis, we see the activation of signalling pathways classically associated with EndMT initiation and mesenchymal development, including TGFβ superfamily9,10,67, WNT18, VEGF68,69, and FGF70 signalling.”

    From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [69]

    The Introduction and Discussion (pages not specified) link VEGF signalling to endocardial cushion growth and endothelial-cell proliferation, supporting its relevance to valve development. They also describe VEGF as a potent inhibitor of EMT during initial cushion formation, so this source does not support VEGF activation as promoting EndMT initiation. The NicheNet result is presented as the citing authors’ own analysis, not as a finding of this paper. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 32

  1. [1]Garg V Muth AN Ransom JF Schluterman MK Barnes R King IN Grossfeld PD Srivastava D Mutations in NOTCH1 cause aortic valve disease Nature 2005 437 270 4 16025100
  2. [2]Person AD Klewer SE Runyan RB Cell biology of cardiac cushion development Int Rev Cytol 2005 243 287 335 15797462
  3. [3]Hinton RB Jr Lincoln J Deutsch GH Osinska H Manning PB Benson DW Yutzey KE Extracellular matrix remodeling and organization in developing and diseased aortic valves Circ Res 2006 98 1431 8 16645142
  4. [4]Lincoln J Alfieri CM Yutzey KE Development of heart valve leaflets and supporting apparatus in chicken and mouse embryos Dev Dyn 2004 230 239 50 15162503
  5. [5]Lange AW Yutzey KE NFATc1 expression in the developing heart valves is responsive to the RANKL pathway and is required for endocardial expression of cathepsin K Dev Biol 2006 292 407 17 16680826
  6. [6]Armstrong EJ Bischoff J Heart valve development: endothelial cell signaling and differentiation Circ Res 2004 95 459 70 15345668 PMC2810618
  7. [7]Chang CP Neilson JR Bayle JH Gestwicki JE Kuo A Stankunas K Graef IA Crabtree GR A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis Cell 2004 118 649 63 15339668
  8. [8]Macian F Garcia-Rodriguez C Rao A Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun Embo J 2000 19 4783 95 10970869 PMC302068
  9. [9]de la Pompa JL Timmerman LA Takimoto H Yoshida H Elia AJ Samper E Potter J Wakeham A Marengere L Langille BL Crabtree GR Mak TW Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum Nature 1998 392 182 6 9515963
  10. [10]Liberatore CM Yutzey KE Calcineurin signaling in avian cardiovascular development Dev Dyn 2004 229 300 11 14745954
  11. [11]Ranger AM Grusby MJ Hodge MR Gravallese EM de la Brousse FC Hoey T Mickanin C Baldwin HS Glimcher LH The transcription factor NF-ATc is essential for cardiac valve formation Nature 1998 392 186 90 9515964
  12. [12]Cleaver O Melton DA Endothelial signaling during development Nat Med 2003 9 661 8 12778164
  13. [13]Ferrara N Gerber HP LeCouter J The biology of VEGF and its receptors Nat Med 2003 9 669 76 12778165
  14. [14]Miquerol L Gertsenstein M Harpal K Rossant J Nagy A Multiple developmental roles of VEGF suggested by a LacZ-tagged allele Dev Biol 1999 212 307 22 10433823
  15. [16]Johnson EN Lee YM Sander TL Rabkin E Schoen FJ Kaushal S Bischoff J NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells J Biol Chem 2003 278 1686 92 12427739 PMC2813494
  16. [18]Theoleyre S Wittrant Y Tat SK Fortun Y Redini F Heymann D The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling Cytokine Growth Factor Rev 2004 15 457 75 15561602
  17. [19]Rabkin E Aikawa M Stone JR Fukumoto Y Libby P Schoen FJ Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves Circulation 2001 104 2525 32 11714645
  18. [20]Hamburger V Hamilton H A series of normal stages in the development of the chick embryo J of Morphol 1951 88 49 92 24539719
  19. [21]Lincoln J Alfieri CM Yutzey KE BMP and FGF regulatory pathways control cell lineage diversification of heart valve precursor cells Dev Biol 2006 292 290 302 16680829
  20. [22]Ehrman LA Yutzey KE Lack of regulation in the heart forming region of avian embryos Dev Biol 1999 207 163 75 10049572
  21. [23]Shelton EL Yutzey KE Tbx20 regulation of endocardial cushion cell proliferation and extracellular matrix gene expression Dev Biol 2007 302 376 88 17064679 PMC1847324
  22. [24]Lefebvre V Dumitriu B Penzo-Mendez A Han Y Pallavi B Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors Int J Biochem Cell Biol 2007 39 2195 214 17625949 PMC2080623
  23. [25]Armesilla AL Lorenzo E Gomez del Arco P Martinez-Martinez S Alfranca A Redondo JM Vascular endothelial growth factor activates nuclear factor of activated T cells in human endothelial cells: a role for tissue factor gene expression Mol Cell Biol 1999 19 2032 43 10022890 PMC83996
  24. [26]Steinmetz M Skowasch D Wernert N Welsch U Preusse CJ Welz A Nickenig G Bauriedel G Differential profile of the OPG/RANKL/RANK-system in degenerative aortic native and bioprosthetic valves J Heart Valve Dis 2008 17 187 93 18512489
  25. [27]Rodgers LS Lalani S Hardy KM Xiang X Broka D Antin PB Camenisch TD Depolymerized hyaluronan induces vascular endothelial growth factor, a negative regulator of developmental epithelial-to-mesenchymal transformation Circ Res 2006 99 583 9 16931798
  26. [28]Schweighofer B Schultes J Pomyje J Hofer E Signals and genes induced by angiogenic growth factors in comparison to inflammatory cytokines in endothelial cells Clin Hemorheol Microcirc 2007 37 57 62 17641395 PMC3103851
  27. [29]Crabtree GR Olson EN NFAT signaling: choreographing the social lives of cells Cell 2002 109 Suppl S67 79 11983154
  28. [30]Graef IA Chen F Crabtree GR NFAT signaling in vertebrate development Curr Opin Genet Dev 2001 11 505 12 11532391
  29. [31]Hogan PG Chen L Nardone J Rao A Transcriptional regulation by calcium, calcineurin, and NFAT Genes Dev 2003 17 2205 32 12975316
  30. [32]Craig EA Stevens MV Vaillancourt RR Camenisch TD MAP3Ks as central regulators of cell fate during development Dev Dyn 2008 237 3102 14 18855897
  31. [33]Krenz M Yutzey KE Robbins J Noonan syndrome mutation Q79R in Shp2 increases proliferation of valve primordia mesenchymal cells via extracellular signal-regulated kinase 1/2 signaling Circ Res 2005 97 813 20 16166557 PMC1388074
  32. [34]Stevens MV Broka DM Parker P Rogowitz E Vaillancourt RR Camenisch TD MEKK3 initiates transforming growth factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis Circ Res 2008 103 1430 40 19008476 PMC2728220

Cited by

Sorted by citations

Authors
Combs, M. D., & Yutzey, K. E.
Affiliations
Cincinnati Children's Hospital Medical Center (US)
ORCID
Yutzey, Katherine E.
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2009-09-11
Volume
105
Issue
6
Pages
565-574
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.109.196469
PMC
PMC2749238
OpenAlex
W2074238996
Cited by
76
References
2
Citations by year
2026: 2 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 8 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 6 · 2015: 1 · 2014: 7 · 2013: 7 · 2012: 4
FWCI
3.62
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5p50hl074728-05)
  • National Heart, Lung, and Blood Institute (P50-HL074728)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
NFATc1, heart valve development, endocardial cushion, vascular endothelial growth factor, RANKL, calcineurin, JNK1/2 signaling, cathepsin K, extracellular matrix remodeling, endothelial cell proliferation, chick embryo
MeSH terms
Animals, Cathepsins, Chick Embryo, Extracellular Matrix, Heart Valves, Mice, Mutant Strains, Calcineurin, Mitogen-Activated Protein Kinase 1, MAP Kinase Signaling System, Vascular Endothelial Growth Factor A, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, MAP Kinase Kinase 1, Cell Proliferation, NFATC Transcription Factors, Mice, RANK Ligand, Endocardial Cushions, Cathepsin K

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review