Molecular phenotyping and functional assessment of smooth muscle-like cells with pathogenic variants in aneurysm genes ACTA2, MYH11, SMAD3 and FBN1

Joyce Burger, Natalija Bogunovic, Nathalie P. De Wagenaar, Hui Liu, Nicole Van Vliet, Arne Ijpma, Alessandra Maugeri, Dimitra Micha, Hence J.M. Verhagen, Timo L.M. Ten Hagen, Danielle Majoor-Krakauer, Ingrid Van Der Pluijm, Jeroen Essers*, Kak K. Yeung

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Aortic aneurysms (AAs) are pathological dilatations of the aorta. Pathogenic variants in genes encoding for proteins of the contractile machinery of vascular smooth muscle cells (VSMCs), genes encoding proteins of the transforming growth factor beta signaling pathway and extracellular matrix (ECM) homeostasis play a role in the weakening of the aortic wall. These variants affect the functioning of VSMC, the predominant cell type in the aorta. Many variants have unknown clinical significance, with unknown consequences on VSMC function and AA development. Our goal was to develop functional assays that show the effects of pathogenic variants in aneurysm-related genes. We used a previously developed fibroblast transdifferentiation protocol to induce VSMC-like cells, which are used for all assays. We compared transdifferentiated VSMC-like cells of patients with a pathogenic variant in genes encoding for components of VSMC contraction (ACTA2, MYH11), transforming growth factor beta (TGFβ) signaling (SMAD3) and a dominant negative (DN) and two haploinsufficient variants in the ECM elastic laminae (FBN1) to those of healthy controls. The transdifferentiation efficiency, structural integrity of the cytoskeleton, TGFβ signaling profile, migration velocity and maximum contraction were measured. Transdifferentiation efficiency was strongly reduced in SMAD3 and FBN1 DN patients. ACTA2 and FBN1 DN cells showed a decrease in SMAD2 phosphorylation. Migration velocity was impaired for ACTA2 and MYH11 cells. ACTA2 cells showed reduced contractility. In conclusion, these assays for showing effects of pathogenic variants may be promising tools to help reclassification of variants of unknown clinical significance in AA-related genes.

Original languageEnglish
Pages (from-to)2286-2299
Number of pages14
JournalHuman Molecular Genetics
Issue number23
Publication statusPublished - 1 Dec 2021

Bibliographical note

The authors would like to thank Stichting Lijf en Leven (Genexpressie analyse ter detective van de moleculaire mechanismen van aneurysmavorming—GAMMA), Erasmus MC Mrace grant and Amsterdam Cardiovascular Sciences Institute (ICaR AiO 2015 PhD grant) for supporting this research.

Publisher Copyright:
© 2021 The Author(s) 2021.


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