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MicroRNA miR145 regulates TGFBR2 expression and matrix synthesis in vascular smooth muscle cells.

ABSTRACT: MicroRNA miR145 has been implicated in vascular smooth muscle cell differentiation, but its mechanisms of action and downstream targets have not been fully defined.Here, we sought to explore and define the mechanisms of miR145 function in smooth muscle cells.Using a combination of cell culture assays and in vivo mouse models to modulate miR145, we characterized its downstream actions on smooth muscle phenotypes. Our results show that the miR-143/145 gene cluster is induced in smooth muscle cells by coculture with endothelial cells. Endothelial cell-induced expression of miR-143/145 is augmented by Notch signaling and accordingly expression is reduced in Notch receptor-deficient cells. Screens to identify miR145-regulated genes revealed that the transforming growth factor (TGF)-? pathway has a significantly high number of putative target genes, and we show that TGF? receptor II is a direct target of miR145. Extracellular matrix genes that are regulated by TGF? receptor II were attenuated by miR145 overexpression, and miR145 mutant mice exhibit an increase in extracellular matrix synthesis. Furthermore, activation of TGF? signaling via angiotensin II infusion revealed a pronounced fibrotic response in the absence of miR145.These data demonstrate a specific role for miR145 in the regulation of matrix gene expression in smooth muscle cells and suggest that miR145 acts to suppress TGF?-dependent extracellular matrix accumulation and fibrosis, while promoting TGF?-induced smooth muscle cell differentiation. Our findings offer evidence to explain how TGF? signaling exhibits distinct downstream actions via its regulation by a specific microRNA.

SUBMITTER: Zhao N

PROVIDER: S-EPMC4299754 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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MicroRNA miR145 regulates TGFBR2 expression and matrix synthesis in vascular smooth muscle cells.

Zhao Ning N Koenig Sara N SN Trask Aaron J AJ Lin Cho-Hao CH Hans Chetan P CP Garg Vidu V Lilly Brenda B

Circulation research 20141016 1

<h4>Rationale</h4>MicroRNA miR145 has been implicated in vascular smooth muscle cell differentiation, but its mechanisms of action and downstream targets have not been fully defined.<h4>Objective</h4>Here, we sought to explore and define the mechanisms of miR145 function in smooth muscle cells.<h4>Methods and results</h4>Using a combination of cell culture assays and in vivo mouse models to modulate miR145, we characterized its downstream actions on smooth muscle phenotypes. Our results show tha ...[more]

PMID: 25323858

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Project description:ObjectiveWe examined the role of syndecan-1 in modulating the phenotype of vascular smooth muscle cells in the context of endogenous inflammatory factors and altered microenvironments that occur in disease or injury-induced vascular remodeling.Methods and resultsVascular smooth muscle cells (vSMCs) display a continuum of phenotypes that can be altered during vascular remodeling. While the syndecans have emerged as powerful and complex regulators of cell function, their role in controlling vSMC phenotype is unknown. Here, we isolated vSMCs from wild type (WT) and syndecan-1 knockout (S1KO) mice. Gene expression and western blotting studies indicated decreased levels of α-smooth muscle actin (α-SMA), calponin, and other vSMC-specific differentiation markers in S1KO relative to WT cells. The spread area of the S1KO cells was found to be greater than WT cells, with a corresponding increase in focal adhesion formation, Src phosphorylation, and alterations in actin cytoskeletal arrangement. In addition, S1KO led to increased S6RP phosphorylation and decreased AKT and PKC-α phosphorylation. To examine whether these changes were present in vivo, isolated aortae from aged WT and S1KO mice were stained for calponin. Consistent with our in-vitro findings, the WT mice aortae stained higher for calponin relative to S1KO. When exposed to the inflammatory cytokine TNF-α, WT vSMCs had an 80% reduction in syndecan-1 expression. Further, with TNF-α, S1KO vSMCs produced increased pro-inflammatory cytokines relative to WT. Finally, inhibition of interactions between syndecan-1 and integrins αvβ3 and αvβ5 using the inhibitory peptide synstatin appeared to have similar effects on vSMCs as knocking out syndecan-1, with decreased expression of vSMC differentiation markers and increased expression of inflammatory cytokines, receptors, and osteopontin.ConclusionsTaken together, our results support that syndecan-1 promotes vSMC differentiation and quiescence. Thus, the presence of syndecan-1 would have a protective effect against vSMC dedifferentiation and this activity is linked to interactions with integrins αvβ3 and αvβ5.

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MicroRNA miR145 regulates TGFBR2 expression and matrix synthesis in vascular smooth muscle cells.

Publications

MicroRNA miR145 regulates TGFBR2 expression and matrix synthesis in vascular smooth muscle cells.

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