Evidence map›Paper›PMID 39793757›Full record

ArticleJournal of molecular and cellular cardiology2025

Vinculin haploinsufficiency impairs integrin-mediated costamere remodeling on stiffer microenvironments.

Aileena C Nelson, Thomas G Molley, Gisselle Gonzalez, Natalie J Kirkland, Alyssa R Holman, Evan M Masutani, Neil C Chi, Adam J Engler

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of molecular and cellular cardiology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

8 authors.

Aileena C NelsonDivision of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
Thomas G MolleyDivision of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Gisselle GonzalezDivision of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Natalie J KirklandShu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
Alyssa R HolmanDivision of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Evan M MasutaniShu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
Neil C ChiDivision of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Institute of Engineering Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: nchi@health.ucsd.edu.
Adam J EnglerShu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Institute of Engineering Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA. Electronic address: aengler@ucsd.edu.

Funding

PREDOCTORAL TRAINING PROGRAM IN GENETICST32GM007388 · NIGMS · PRINCETON UNIVERSITY · PI CRISTEA, ILEANA M. · 1985 to 2022
$27.4M
Training In Cardiovascular Physiology & PharmacologyT32HL007444 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Ju Chen, Robert Scott Ross · 1985 to 2026
$11.1M
Training Program in Basic Clinical GeneticsT32GM008666 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HAMILTON, BRUCE A · 1998 to 2021
$8.6M
Mechanisms of vascular pathology from abnormal protein kinase G signalingR01HL132141 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI PILZ, RENATE B · 2016 to 2025
$4.5M
Mechanogenetics: An Integrated Approach to Aging in Muscle DysfunctionR01AG045428 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ENGLER, ADAM J · 2013 to 2022
$3.4M
Investigation of cellular cues for differentiation of ventricular cardiomyocytesF31HL163996 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HOLMAN, ALYSSA RAE · 2022 to 2023
$79k
Harnessing biophysical cues to spatially organize developing cardiac organoidsF32HL176176 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MOLLEY, THOMAS GREGORY · 2024 to 2024
$74k
NHLBI NIH HHS F31 HL163996NHLBI NIH HHS F32 HL176176NHLBI NIH HHS R01 HL132141NHLBI NIH HHS T32 HL007444NIA NIH HHS R01 AG045428NIGMS NIH HHS T32 GM007388NIGMS NIH HHS T32 GM008666
6 · The paper itself

Abstract

Vinculin (VCL) is a key adapter protein located in force-bearing costamere complexes, which mechanically couples the sarcomere to the ECM. Heterozygous vinculin frameshift genetic variants can contribute to cardiomyopathy when external stress is applied, but the mechanosensitive pathways underpinning VCL haploinsufficiency remain elusive. Here, we show that in response to extracellular matrix stiffening, heterozygous loss of VCL disrupts force-mediated costamere protein recruitment, thereby impairing cardiomyocyte contractility and sarcomere organization. Analyses of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) harboring either VCL c.659dupA or VCL c.74del7 heterozygous VCL frameshift variants revealed that these VCL mutant hPSC-CMs exhibited heightened contractile strain energy, morphological maladaptation, and sarcomere disarray on stiffened matrix. Mechanosensitive recruitment of costameric talin 2, paxillin, focal adhesion kinase, and α-actinin was significantly reduced in vinculin variant cardiomyocytes. Despite poorly formed costamere complexes and sarcomeres, elevated expression of integrin β1 and cortical actin on stiff substrates may rescue force transmission on stiff substrates, an effect that is recapitulated in WT CMs by ligating integrin receptors and blocking mechanosensation. Together, these data support that heterozygous loss of VCL contributes to adverse cardiomyocyte remodeling by impairing adhesion-mediated force transmission from the costamere to the cytoskeleton. (191 words).

Indexed as

HaploinsufficiencyIntegrin beta1IntegrinsVinculinExtracellular MatrixHumansMechanotransduction, CellularMyocytes, CardiacPluripotent Stem CellsSarcomeresIntegrin beta1IntegrinsVCL protein, humanVinculinCardiomyocyteContractilityCostamereMechanosensationSarcomeres

Identifiers

PMID39793757
PMCPMC11875886

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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.