SPOCK2-mediated phenotype switch of vascular smooth muscle cells contributes to aortic aneurysm in Kawasaki disease
5 affiliations
- 1Department of Cardiology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University
- 2Department of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents’ Health and Diseases
- 3School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College
- 4Department of Gynecology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University
- 5Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada
Abstract
Background: Coronary artery aneurysm is a major cardiovascular complication of Kawasaki disease (KD). The phenotype switch of vascular smooth muscle cells (VSMCs) plays a crucial role in pathological vascular wall remodeling in KD; however, the molecular mechanisms driving this process remain incompletely understood. Although the SPARC protein family has been implicated in various vascular diseases, the role of specific SPARC family members in mediating VSMC phenotypic transition during KD-associated vasculitis remains unknown. Here, we investigated the function and mechanistic role of SPOCK2, a SPARC family member, in vascular wall homeostasis under KD-induced inflammatory stress.
Methods: SPOCK2 transcript expression was evaluated in public transcriptomic datasets and clinical KD cohorts. To model KD vasculitis in vivo , mice were challenged with Candida albicans water-soluble fraction (CAWS). Adeno-associated virus (AAV)2/9-mediated gene transfer was employed for targeted in vivo overexpression of SPOCK2 in mouse aortas. VSMC phenotypic transition, vascular remodeling, extracellular matrix (ECM) integrity, and local cytokine production were assessed using immunofluorescence, RNA sequencing, quantitative RT-PCR, and co-immunoprecipitation assays to delineate SPOCK2–MMP2 structural and functional interactions.
Results: Transcriptional profiling of clinical KD cohorts revealed that SPOCK2 is consistently downregulated in the acute phase of the disease. In murine KD vasculitis models, SPOCK2 expression was notably depleted in both aortic root and abdominal aorta, correlating with severe vascular inflammation and aneurysm formation. Targeted in vivo overexpression of SPOCK2 via AAV2/9 effectively restored the contractile VSMC phenotype, thereby attenuating vasculitis and preventing abdominal aortic aneurysm formation. Mechanistically, SPOCK2 acts as a specific endogenous inhibitor of MMP2. Through physical interaction, SPOCK2 binds to MMP2, hindering its enzymatic activation. In the inflammatory microenvironment of KD, the pathological loss of SPOCK2 leads to unchecked MMP2 activity, promoting uncontrolled extracellular matrix degradation and pathogenic contractile-to-synthetic transition of VSMCs.
Conclusion: Our findings establish SPOCK2 as a novel protective factor in vascular wall homeostasis and a potential candidate for preventive strategies targeting vascular remodeling and systemic vasculitis in Kawasaki disease.
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BibTeX
@article{xu2026spock2mediated,
title = {{SPOCK2-mediated phenotype switch of vascular smooth muscle cells contributes to aortic aneurysm in Kawasaki disease}},
author = {Xiao Xu and Yucong Wei and Min Wang and Jiahui Liu and Ting Zhao and Xian Ma and Tielong Chen and Buddhadeb Dawn and Fangqi Gong and Lin Zhao},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1902009},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1902009/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SPOCK2-mediated phenotype switch of vascular smooth muscle cells contributes to aortic aneurysm in Kawasaki disease
AU - Xiao Xu
AU - Yucong Wei
AU - Min Wang
AU - Jiahui Liu
AU - Ting Zhao
AU - Xian Ma
AU - Tielong Chen
AU - Buddhadeb Dawn
AU - Fangqi Gong
AU - Lin Zhao
PY - 2026
DA - 2026/10/23
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1902009
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1902009/full
AB - Background: Coronary artery aneurysm is a major cardiovascular complication of Kawasaki disease (KD). The phenotype switch of vascular smooth muscle cells (VSMCs) plays a crucial role in pathological vascular wall remodeling in KD; however, the molecular mechanisms driving this process remain incompletely understood. Although the SPARC protein family has been implicated in various vascular diseases, the role of specific SPARC family members in mediating VSMC phenotypic transition during KD-associated vasculitis remains unknown. Here, we investigated the function and mechanistic role of SPOCK2, a SPARC family member, in vascular wall homeostasis under KD-induced inflammatory stress. Methods: SPOCK2 transcript expression was evaluated in public transcriptomic datasets and clinical KD cohorts. To model KD vasculitis in vivo , mice were challenged with Candida albicans water-soluble fraction (CAWS). Adeno-associated virus (AAV)2/9-mediated gene transfer was employed for targeted in vivo overexpression of SPOCK2 in mouse aortas. VSMC phenotypic transition, vascular remodeling, extracellular matrix (ECM) integrity, and local cytokine production were assessed using immunofluorescence, RNA sequencing, quantitative RT-PCR, and co-immunoprecipitation assays to delineate SPOCK2–MMP2 structural and functional interactions. Results: Transcriptional profiling of clinical KD cohorts revealed that SPOCK2 is consistently downregulated in the acute phase of the disease. In murine KD vasculitis models, SPOCK2 expression was notably depleted in both aortic root and abdominal aorta, correlating with severe vascular inflammation and aneurysm formation. Targeted in vivo overexpression of SPOCK2 via AAV2/9 effectively restored the contractile VSMC phenotype, thereby attenuating vasculitis and preventing abdominal aortic aneurysm formation. Mechanistically, SPOCK2 acts as a specific endogenous inhibitor of MMP2. Through physical interaction, SPOCK2 binds to MMP2, hindering its enzymatic activation. In the inflammatory microenvironment of KD, the pathological loss of SPOCK2 leads to unchecked MMP2 activity, promoting uncontrolled extracellular matrix degradation and pathogenic contractile-to-synthetic transition of VSMCs. Conclusion: Our findings establish SPOCK2 as a novel protective factor in vascular wall homeostasis and a potential candidate for preventive strategies targeting vascular remodeling and systemic vasculitis in Kawasaki disease.
SN - 1664-3224
ER -