Highlights
- •ADAM22, a novel regulator of VSMCs, is dramatically upregulated during the development of neointima formation.
- •ADAM22 enhances neointima formation by promoting VSMC proliferation, migration and phenotypic switching.
- •The exacerbating function of ADAM22 in vascular remodeling is largely dependent on activating ERK signaling.
Abstract
Background and aims
Despite the advantage of arterial expansion for life-threatening vascular pathologies,
the occurrence of neointima formation remains a prominent complication, with the underlying
mechanisms largely unknown. A disintegrin and metalloprotease 22 (ADAM22) belongs
to the family of ADAMs that possesses various biological capacities regulating vascular
physiopathology. However, little is known about ADAM22 in vascular smooth muscle cell
(VSMC)-mediated neointima formation. Here, we aimed to evaluate the potential functional
regulation of ADAM22 in neointima formation and to further explore the underlying
mechanisms.
Methods
In our study, platelet-derived growth factor-BB (PDGF-BB)-induced VSMC proliferation
was examined using a 5-bromo-2′-deoxyuridine (BrdU) incorporation assay and a cell
counting kit-8 (CCK8) assay, while VSMC migration was detected using a modified Boyden
chamber method and a scratch-wound assay. The functional role of ADAM22 in neointima
formation was evaluated based on a left carotid artery wire injury model in mice at
14 and 28 days.
Results
ADAM22 was significantly up-regulated in both PDGF-BB-challenged VSMCs and restenotic
arteries of mice. When ADAM22 was overexpressed in VSMCs, cell proliferation, migration
and phenotypic switching were simultaneously aggravated, whereas the opposite was
observed when ADAM22 was knocked down in vitro. In ADAM22 heterozygote mice, wire-injury induced neointima formation was significantly
ameliorated compared to wild-type control mice. Mechanistically, significantly up-regulated
ERK phosphorylation is closely involved in the regulatory effects of ADAM22 in neointima
formation. Interestingly, an ERK inhibitor largely reversed the aggravated VSMCs migration,
proliferation and phenotypic switching induced by ADAM22 overexpression.
Conclusions
Our results indicate that ADAM22 accelerates neointima formation by enhancing VSMC
migration, proliferation and phenotypic switching via promoting ERK phosphorylation.
Suppressing ADAM22 expression may be an effective strategy for ameliorating neointima
formation.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: February 11, 2019
Accepted:
February 1,
2019
Received in revised form:
December 30,
2018
Received:
September 21,
2018
Identification
Copyright
© 2019 Published by Elsevier B.V.
