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Thrombospondin 2 (TSP2) Mitigates Abdominal Aortic Aneurysm via Modulating Extracellular Matrix Remodeling

This article is a preprint and has not been certified by peer review.

Authors

    Lanting Hu,  
    Lanting Hu
    • The Second Affiliated Hospital,School of Medicine,Zhejiang University
    Li Yin,  
    Li Yin
    • The Second Affiliated Hospital,School of Medicine,Zhejiang University
    Yongli Ji,  
    Yongli Ji
    • The Second Affiliated Hospital,School of Medicine,Zhejiang University
    Naiji Yu,  
    Naiji Yu
    Jianing Yue,  
    Jianing Yue
    Kaijie Zhang,  
    Kaijie Zhang
    Hongzhang Mei,  
    Hongzhang Mei
    Yunlu Chen,  
    Yunlu Chen
    • Zhejiang University School of Medicine
    Jinyi Chen,  
    Jinyi Chen
    • The Second Affiliated Hospital, School of Medicine, Zhejiang University
    Weiwei Zhang,  
    Weiwei Zhang
    • The Second Affiliated Hospital,School of Medicine,Zhejiang University
    Kai Cao,  
    Kai Cao
    • The Second Affiliated Hospital,School of Medicine,Zhejiang University
    Hanlei Zhou,  
    Hanlei Zhou
    • The Second Affiliated Hospital,School of Medicine,Zhejiang University
    Cuiping Xie,  
    Cuiping Xie
    • The Second Affiliated Hospital,School of Medicine,Zhejiang University
    Yunxia Gong,  
    Yunxia Gong
    • The Second Affiliated Hospital,School of Medicine,Zhejiang University
    Lihong Chen,  
    Lihong Chen
    • Bingjiang Institute of Zhejiang University
    Liya Lin,  
    Liya Lin
    • Binjiang Institute of Zhejing University
    Da Huang,  
    Da Huang
    • The Second Affiliated Hospital,School of Medicine,Zhejiang University
    Maryam Maleki Goli,  
    Maryam Maleki Goli
    Parnia Ghanad,  
    Parnia Ghanad
    Jian Shen,  
    Jian Shen
    • The Second Affiliated Hospital,School of Medicine,Zhejiang University
    Lu Zhao,  
    Lu Zhao
    Bowen Wang,  
    Bowen Wang
    Zhenjie Liu
    Zhenjie Liu
Categories
Physiology & Pathology
Keywords
Abdominal aortic aneurysm; Thrombospondin-2; Extracellular matrix remodeling; Adventitial fibroblasts; Akt/STAT3 signaling

Abstract

Abdominal aortic aneurysm (AAA) is a lethal yet prevalent vascular disease, featuring progressive extracellular matrix (ECM) degradation and aortic dilation. Despite its high mortality upon rupture, there are still no medical treatments with proven benefits for AAA. In the current study, we identified thrombospondin-2 (TSP2) as a critical modulator against ECM degradation in AAA. Utilizing specimens from patients undergoing open AAA repairs, we observed that both aortic and circulating TSP2 levels were significantly upregulated and positively correlated with aortic wall thickness. Single-cell RNA sequencing and immunofluorescence staining further localized TSP2 primarily to adventitial fibroblasts. Using transgenic whole-body knockout mice, TSP2 deletion accelerated elastase-induced AAA growth, heightened rupture incidence, and exacerbated collagen loss and elastin disruption. Conversely, lentivirus-mediated TSP2 re-introduction in whole-body knockout mice effectively rescued ECM integrity and aortic homeostasis. Mechanistically, chromatin-immunoprecipitation and gain-/loss-of-function studies identified Akt-dependent phosphorylation of STAT3 as a direct transcriptional driver of TSP2. Therapeutically, local delivery of exogenous TSP2 via peri-aortic hydrogel effectively mitigated ECM destruction and AAA formation. Collectively, our current study study established TSP2 as a fibroblast-derived stabilizer of vascular ECM and highlighted its therapeutic potential for AAA through targeted modulation of matrix remodeling pathways.

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DOI:

https://doi.org/10.65215/LTSpreprints.2026.04.28.000211

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2026-04-28

How to Cite

Hu, L., Yin, L., Ji, Y., Yu, N., Yue, J., Zhang, K., Mei, H., Chen, Y., Chen, J., Zhang, W., Cao, K., Zhou, H., Xie, C., Gong, Y., Chen, L., Lin, L., Huang, D., Goli, M. M., Ghanad, P., … Liu, Z. (2026). Thrombospondin 2 (TSP2) Mitigates Abdominal Aortic Aneurysm via Modulating Extracellular Matrix Remodeling. LangTaoSha Preprint Server. https://doi.org/10.65215/LTSpreprints.2026.04.28.000211

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