Effects of Extracellular Matrix Softening on Vascular Smooth Muscle Cell Dysfunction

Yihui Shao, Guoqi Li, Shan Huang, Zhenfeng Li, Bokang Qiao, Duanduan Chen, Yulin Li, Huirong Liu*, Jie Du*, Ping Li*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Vascular smooth muscle cells (VSMCs) shift from a physiological contractile phenotype to an adverse proliferative or synthetic state, which is a major event leading to aortic disease. VSMCs are exposed to multiple mechanical signals from their microenvironment including vascular extracellular matrix (ECM) stiffness and stretch which regulate VSMC contraction. How ECM stiffness regulates the function and phenotype of VSMCs is not well understood. In this study, we introduce in vitro and in vivo models to evaluate the impact of ECM stiffnesses on VSMC function. Through unbiased transcriptome sequencing analysis, we detected upregulation of synthetic phenotype-related genes including osteopontin, matrix metalloproteinases, and inflammatory cytokines in VSMCs cultured using soft matrix hydrogels in vitro, suggesting VSMC dedifferentiation toward a synthetic phenotype upon ECM softening. For the in vivo model, the lysyl oxidase inhibitor β-aminopropionitrile monofumarate (BAPN) was administrated to disrupt the cross-linking of collagen to induce ECM softening. Consistently, decreased ECM stiffnesses promoted VSMC phenotypic switching to a synthetic phenotype as evidenced by upregulation of synthetic phenotype-related genes in the aortas of mice following BAPN treatment. Finally, BAPN-treated mice showed severe expansion and developed aortic dissection. Our study reveals the pivotal role of ECM softening in regulating the VSMC phenotype switch and provides a potential target for treating VSMC dysfunction and aortic dissection disease.

Original languageEnglish
Pages (from-to)548-556
Number of pages9
JournalCardiovascular Toxicology
Volume20
Issue number6
DOIs
Publication statusPublished - 1 Dec 2020

Keywords

  • Extracellular matrix
  • Synthetic phenotype
  • Vascular smooth muscle cell

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