TY - JOUR
T1 - Vascular smooth muscle cell senescence accelerates medin aggregation via small extracellular vesicle secretion and extracellular matrix reorganization
AU - Shanahan, Cathy
N1 - Funding Information:
This study was supported by British Heart Foundation programme grant (RG/17/2/32808) and BHF MRes/PhD studentship. This work was also supported in part by BHF grant PG/16/18/32070 (to DM and JM). MM is a BHF Chair Holder (CH/16/3/32406) with BHF programme grant support (RG/16/14/32397, RG/F/21/110053). MM's research was made possible through the support of the BIRAX Ageing Initiative. The microscopy was performed at the Wohl Cellular Imaging Centre at King's College London. The proteomics of EVs was performed by Xiaoping Yang and Steven Lynham at the Denmark Hill Proteomics Facility. Graphical abstract created with BioRender.com .
Funding Information:
This study was supported by British Heart Foundation programme grant (RG/17/2/32808) and BHF MRes/PhD studentship. This work was also supported in part by BHF grant PG/16/18/32070 (to DM and JM). MM is a BHF Chair Holder (CH/16/3/32406) with BHF programme grant support (RG/16/14/32397, RG/F/21/110053). MM's research was made possible through the support of the BIRAX Ageing Initiative. The microscopy was performed at the Wohl Cellular Imaging Centre at King's College London. The proteomics of EVs was performed by Xiaoping Yang and Steven Lynham at the Denmark Hill Proteomics Facility. Graphical abstract created with BioRender.com.
Publisher Copyright:
© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
PY - 2023/2
Y1 - 2023/2
N2 - Vascular amyloidosis, caused when peptide monomers aggregate into insoluble amyloid, is a prevalent age-associated pathology. Aortic medial amyloid (AMA) is the most common human amyloid and is composed of medin, a 50-amino acid peptide. Emerging evidence has implicated extracellular vesicles (EVs) as mediators of pathological amyloid accumulation in the extracellular matrix (ECM). To determine the mechanisms of AMA formation with age, we explored the impact of vascular smooth muscle cell (VSMC) senescence, EV secretion, and ECM remodeling on medin accumulation. Medin was detected in EVs secreted from primary VSMCs. Small, round medin aggregates colocalized with EV markers in decellularized ECM in vitro and medin was shown on the surface of EVs deposited in the ECM. Decreasing EV secretion with an inhibitor attenuated aggregation and deposition of medin in the ECM. Medin accumulation in the aortic wall of human subjects was strongly correlated with age and VSMC senescence increased EV secretion, increased EV medin loading and triggered deposition of fibril-like medin. Proteomic analysis showed VSMC senescence induced changes in EV cargo and ECM composition, which led to enhanced EV-ECM binding and accelerated medin aggregation. Abundance of the proteoglycan, HSPG2, was increased in the senescent ECM and colocalized with EVs and medin. Isolated EVs selectively bound to HSPG2 in the ECM and its knock-down decreased formation of fibril-like medin structures. These data identify VSMC-derived EVs and HSPG2 in the ECM as key mediators of medin accumulation, contributing to age-associated AMA development.
AB - Vascular amyloidosis, caused when peptide monomers aggregate into insoluble amyloid, is a prevalent age-associated pathology. Aortic medial amyloid (AMA) is the most common human amyloid and is composed of medin, a 50-amino acid peptide. Emerging evidence has implicated extracellular vesicles (EVs) as mediators of pathological amyloid accumulation in the extracellular matrix (ECM). To determine the mechanisms of AMA formation with age, we explored the impact of vascular smooth muscle cell (VSMC) senescence, EV secretion, and ECM remodeling on medin accumulation. Medin was detected in EVs secreted from primary VSMCs. Small, round medin aggregates colocalized with EV markers in decellularized ECM in vitro and medin was shown on the surface of EVs deposited in the ECM. Decreasing EV secretion with an inhibitor attenuated aggregation and deposition of medin in the ECM. Medin accumulation in the aortic wall of human subjects was strongly correlated with age and VSMC senescence increased EV secretion, increased EV medin loading and triggered deposition of fibril-like medin. Proteomic analysis showed VSMC senescence induced changes in EV cargo and ECM composition, which led to enhanced EV-ECM binding and accelerated medin aggregation. Abundance of the proteoglycan, HSPG2, was increased in the senescent ECM and colocalized with EVs and medin. Isolated EVs selectively bound to HSPG2 in the ECM and its knock-down decreased formation of fibril-like medin structures. These data identify VSMC-derived EVs and HSPG2 in the ECM as key mediators of medin accumulation, contributing to age-associated AMA development.
UR - http://www.scopus.com/inward/record.url?scp=85142743365&partnerID=8YFLogxK
U2 - 10.1111/acel.13746
DO - 10.1111/acel.13746
M3 - Article
SN - 1474-9718
VL - 22
JO - AGING CELL
JF - AGING CELL
IS - 2
M1 - e13746
ER -