Effects of Extracellular Matrix Softening on Vascular Smooth Muscle Cell Dysfunction
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Effects of Extracellular Matrix Softening on Vascular Smooth Muscle Cell Dysfunction Yihui Shao1,2,3 · Guoqi Li2,3 · Shan Huang2,3 · Zhenfeng Li4 · Bokang Qiao2,3 · Duanduan Chen4 · Yulin Li2,3 · Huirong Liu1 · Jie Du2,3 · Ping Li2,3
© Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Extracellular matrix · Vascular smooth muscle cell · Synthetic phenotype
Introduction Handling editor: Yu-Ming Kang * Huirong Liu [email protected] * Jie Du [email protected] * Ping Li [email protected] 1
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
2
Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, China
3
Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, China
4
School of Life Science, Beijing Institute of Technology, Beijing 100081, China
Vascular smooth muscle cells (VSMCs) are key cells in the vascular wall and are responsible for regulating blood vessel homeostasis [1]. VSMCs have diverse function and phenotype depending on their environmental cues [2]. Switching of VSMCs from a physiological contractile phenotype to an adverse proliferative, synthetic and inflammatory state is a major initiating event leading to atherosclerosis or aortic aneurysm disease [3, 4]. Multiple mechanical cues including extracellular matrix stiffness
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