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

doi:10.1016/j.yjmcc.2025.01.001

Vinculin haploinsufficiency impairs integrin-mediated costamere remodeling on stiffer microenvironments

J Mol Cell Cardiol. 2025 Jan 8:S0022-2828(25)00001-X. doi: 10.1016/j.yjmcc.2025.01.001. Online ahead of print.

Authors

Aileena C Nelson¹, Thomas G Molley², Gisselle Gonzalez², Natalie J Kirkland³, Alyssa R Holman⁴, Evan M Masutani³, Neil C Chi⁵, Adam J Engler⁶

Affiliations

¹ Division 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.
² Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³ 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.
⁴ Division 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.
⁵ Division 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: [email protected].
⁶ 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; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA. Electronic address: [email protected].

PMID: 39793757
DOI: 10.1016/j.yjmcc.2025.01.001

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).

Keywords: Cardiomyocyte; Contractility; Costamere; Mechanosensation; Sarcomeres.