Highlights
- •A large mount of exosomes were present in adventitia of aneurysmal tiusses, and mainly from macrophages.
- •GW4869, an inhibitor of exosome biogenesis, significantly reduced dilation of calcium phosphate (CaPO4)-induced AAA.
- •Macrophage-derived exosomes induced MMP-2 expression in vascular smooth muscle cells by activating JNK and p38 pathways.
Abstract
Background and aims
Abdominal aortic aneurysm (AAA) is characterized by infiltration of inflammatory cells,
extracellular matrix (ECM) degradation, and dysfunction of vascular smooth muscle
cells (VSMCs). Recent studies reported that exosomes mediate intercellular communication
and are involved in different diseases. Whether exosomes play a role in AAA is poorly
understood. Hence, this study evaluated the function of exosomes in AAA development.
Methods
The presence of exosomes in human and calcium phosphate (CaPO4)-induced AAA tissues was determined by immunofluorescence staining of CD63 and Alix.
GW4869, an inhibitor of exosome biogenesis, was intraperitoneally injected into CaPO4-induced AAA tissues to evaluate the effects of exosomal inhibition on AAA development.
To explore the underlying mechanisms, the human monocytic cell line THP-1 was differentiated
into macrophages, and exosomes were collected from macrophages. VSMCs were treated
with macrophage-derived exosomes, and the expression of matrix metalloproteinase-2
(MMP-2) was evaluated. The activation of mitogen-activated protein kinases (MAPKs)
pathways was also investigated in vitro and in vivo.
Results
Exosomes were detected in the adventitia of aneurysmal tissues obtained from humans
and mice. They were mainly expressed in clusters of macrophages. Intraperitoneal injection
of GW4869 for two weeks significantly attenuated the progression of CaPO4-induced AAA, preserved elastin integrity and decreased MMP-2 expression. Similarly,
administration of GW4869 suppressed the systemic and aneurysmal exosome generation.
In vitro, treatment with macrophage-derived exosomes elevated MMP-2 expression in human VSMCs,
while pre-treatment with GW4869 abolished these effects. It was also found that JNK
and p38 pathways mediated the production of MMP-2 in VSMCs following treatment with
macrophage-derived exosomes.
Conclusions
This study suggests that exosomes derived from macrophages are involved in the pathogenesis
of AAA. Macrophage-derived exosomes trigger MMP-2 expression in VSMC via JNK and p38
pathways. GW4869 supplementation attenuates CaPO4-induced AAA in mice.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: August 25, 2019
Accepted:
August 23,
2019
Received in revised form:
August 13,
2019
Received:
February 27,
2019
Identification
Copyright
© 2019 Elsevier B.V. All rights reserved.
