Endothelial cells induce degradation of ECM through enhanced secretion of MMP14 carried on extracellular vesicles in venous malformation

Venous malformations (VMs), featuring localized dilated veins, are the most common developmental vascular anomalies. Aberrantly organized perivascular extracellular matrix (ECM) is one of the prominent pathological hallmarks of VMs, accounting for vascular dysfunction. Although previous studies have...

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Bibliographic Details
Published in:Cell and tissue research 2022-09, Vol.389 (3), p.517-530
Main Authors: Chen, Gao-Hong, Yang, Jie-Gang, Xia, Hou-Fu, Zhang, Lin-Zhou, Chen, Yin-Hsueh, Wang, Kui-Ming, Duan, Xu, Wu, Lian-Zhi, Zhao, Yi-Fang, Chen, Gang
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Cell culture
Degradation
Endothelial cells
Endothelium
Extracellular matrix
Extracellular vesicles
Human Genetics
Molecular Medicine
Molecular modelling
Proteins
Proteomics
Regular Article
Secretion
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Summary:Venous malformations (VMs), featuring localized dilated veins, are the most common developmental vascular anomalies. Aberrantly organized perivascular extracellular matrix (ECM) is one of the prominent pathological hallmarks of VMs, accounting for vascular dysfunction. Although previous studies have revealed various proteins involved in ECM remodeling, the detailed pattern and molecular mechanisms underlying the endothelium-ECM interplay have not been fully elucidated. Our previous studies revealed drastically elevated extracellular vesicle (EV) secretion in VM lesions. Here, we identified increased EV-carried MMP14 in lesion fluids of VMs and culture medium of TIE2-L914F mutant endothelial cells (ECs), along with stronger ECM degradation. Knockdown of RAB27A , a required regulator for vesicle docking and fusion, led to decreased secretion of EV-carried MMP14 in vitro. Histochemical analysis further demonstrated a highly positive correlation between RAB27A in the endothelium and MMP14 in the perivascular environment. Therefore, our results proved that RAB27A-regulated secretion of EV-MMP14, as a new pattern of endothelium-ECM interplay, contributed to the development of VMs by promoting ECM degradation.
ISSN:0302-766X
1432-0878
DOI:10.1007/s00441-022-03657-2