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Fibroblast-Secreted Phosphoprotein 1 Mediates Extracellular Matrix Deposition and Inhibits Smooth Muscle Cell Contractility in Marfan Syndrome Aortic Aneurysm

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Abstract

Fibrillin 1 (Fbn1) mutation causes Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. The mechanisms for extracellular matrix (ECM) homeostasis disruption in MFS TAA are unclear. Here, we found ECM-related gene secreted phosphoprotein 1 (Spp1) increased in Fbn1C1041G/+ mice using transcriptome sequencing and a distinct fibroblast subcluster with Spp1 as the strongest marker was identified with analysis of the MFS mouse aortic single-cell sequencing dataset. Immunostaining confirmed elevated Spp1 in adventitial fibroblasts, and Spp1 might regulate fibroblast and smooth muscle cell (SMC) communication primarily through Itga8/Itgb1. Then, we observed Spp1 reduced contractile genes Acta2 and Tagln expression in SMCs and increased collagen expression in fibroblasts, which might contribute to TAA development. Finally, we also found elevated SPP1 plasma level was associated with an increased risk of TAA in patients. Therefore, SPP1 may serve as a biomarker and therapeutic target for TAA.

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Abbreviations

Fbn1:

Fibrillin-1

TAA:

Thoracic aortic aneurysm

ECM:

Extracellular matrix

Spp1:

Secreted phosphoprotein 1

SMC:

Smooth muscle cell

MFS:

Marfan syndrome

Itga8/Itgb1:

Integrin alpha 8/integrin beta 1

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Acknowledgements

We thank Prof. Michael P. Fischbein for the aortic scRNA-seq data of Marfan Syndrome mice and Prof. Dongjin Wang for helping prepare the human aortic aneurysm and arterial tissue samples

Funding

This work was supported by the National Natural Science Foundation of China (81770250, 81930014, 81770470) and the Beijing Young Top-notch Talent Program (2017000021223ZK35).

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Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China

    Mei Zhou & Jie Du

  2. Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Yuexin Zhu, Feiran Qi, Shuai Zheng, Shijuan Gao, Yulin Li, Yan Liu & Jie Du

  3. The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing, 100029, China

    Yuexin Zhu, Feiran Qi, Shuai Zheng, Shijuan Gao, Yulin Li, Yan Liu & Jie Du

  4. Department of Thoracic and Cardiovascular Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Institute of Cardiothoracic Vascular Disease, Nanjing University, Nanjing, 210008, China

    Zeyi Zhou

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Contributions

MZ conceptualized the study, performed experiments, carried out the analyses, and drafted the initial manuscript. YZ performed data analysis. ZZ, FQ, and SZ conducted samples and a part of data collection. SG and YuL supervised the analyses. JD and YaL participated in the study design, reviewed, and revised the manuscript.

Corresponding authors

Correspondence to Yan Liu or Jie Du.

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Ethics Approval

All animal experiments were performed in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals, and the protocols were approved by the Institutional Animal Care and Use Committee of Capital Medical University. Use of human samples was approved by the Medical Ethical Committee of Beijing Anzhen Hospital, Capital Medical University and Affiliated Drum Tower Hospital of Nanjing University Medical School and in concordance with the principles outlined in the Declaration of Helsinki. Informed consent was obtained.

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The authors declare no competing interests.

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Associate Editor Junjie Xiao oversaw the review of this article.

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Zhou, M., Zhu, Y., Zhou, Z. et al. Fibroblast-Secreted Phosphoprotein 1 Mediates Extracellular Matrix Deposition and Inhibits Smooth Muscle Cell Contractility in Marfan Syndrome Aortic Aneurysm. J. of Cardiovasc. Trans. Res. 15, 959–970 (2022). https://doi.org/10.1007/s12265-022-10239-8

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