MiR-26a contributes to the PDGF-BB-induced phenotypic switch of vascular smooth muscle cells by suppressing Smad1

Abstract

The phenotypic switch of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of various vascular diseases, such as atherosclerosis and post-angioplasty restenosis. Small non-coding microRNAs (miRNAs) have emerged as critical modulators of VSMC function. In the present study, miR-26a was significantly increased in cultured VSMCs stimulated by platelet-derived growth factor-BB (PDGF-BB) and in arteries with neointimal lesion formation. Moreover, we demonstrated that miR-26a regulates the expression of VSMC differentiation marker genes such as α-smooth muscle actin (α-SMA), calponin and smooth muscle myosin heavy chain (SM-MHC) in PDGF-BB-treated VSMCs. We further confirmed that the regulatory effect of miR-26a during the phenotypic transition occurs through its target gene Smad1, which is a critical mediator of the pro-contractile signal transmitted by bone morphogenetic protein (BMP) and transforming growth factor-beta (TGF-β). This discovery proposed a new channel for communication between PDGF and the BMP/TGF-β family. We concluded that miR-26a is an important regulator in the PDGF-BB-mediated VSMC phenotypic transition by targeting Smad1. Interventions aimed at miR-26a may be promising in treating numerous proliferative vascular disorders.

MicroRNA regulation of BMP signaling; cross-talk between endothelium and vascular smooth muscle cells

“…Endothelial and mural cells signal through several paracrine pathways to stabilize vessels including the PGFRβ, angiopoietin, TGFβ, and notch pathways to modulate cell-to-cell communication (Mack 2011;Winkler et al 2011).In one of the most important pathways for mural cell recruitment, endothelial cells release PDGF-BB ligands that acts on the mural cell receptor PDGFR-β to initially recruit vSMCs to blood vessels (Benjamin et al 1998;Lindahl et al 1997). There is evidence that miR26 is modulated by PDGF-BB signalling (Yang et al 2017). Yang et al, 2017, recently showed that neointimal hyperplasia results in elevated levels of PDGF-BB and is associated with upregulation of miR26 and the accumulation of vSMC at sites of injury, indicative of increased proliferation.…”

“…There is evidence that miR26 is modulated by PDGF-BB signalling (Yang et al 2017). Yang et al, 2017, recently showed that neointimal hyperplasia results in elevated levels of PDGF-BB and is associated with upregulation of miR26 and the accumulation of vSMC at sites of injury, indicative of increased proliferation. Furthermore, treatment of primary mouse aortic vSMCs with miR26a mimic drives cells to a synthetic vSMC state (Yang et al 2017).…”

“…Yang et al, 2017, recently showed that neointimal hyperplasia results in elevated levels of PDGF-BB and is associated with upregulation of miR26 and the accumulation of vSMC at sites of injury, indicative of increased proliferation. Furthermore, treatment of primary mouse aortic vSMCs with miR26a mimic drives cells to a synthetic vSMC state (Yang et al 2017). Currently the link between increased PDGF-BB and miR26 is unknown, however because PDGF-BB is primarily released by endothelial cells, it should be explored whether it is activated downstream of Smad1 activation.…”

“…miR26 has been identified as a potential regulator of vSMC proliferation, migration and differentiation of vSMCs in vitro (Icli et al 2014;Leeper et al 2011;Bai et al 2011;Yang et al 2017). miR-26a expression is altered during abdominal aortic aneurysm (AAA) and neointimal lesion formation (Leeper et al 2011;Yang et al 2017), and although primarily categorized as endothelial defects, the pathological progression and compromised vessel structure is attributed to a shift in vSMC phenotypes. However, the significance and cell autonomy of these interactions in an intact animal and in context of developing vSMC are largely unknown.…”

The role of microRNAs in the involvement of vascular smooth muscle cells in the development of atherosclerosis

“…In previous studies,it was shown that Smad1 protein expression was significantly decreased in balloon‐injured rat arteries and PDGF‐BB‐treated VSMCs. Anti‐miR‐26a attenuated the inhibitory effect of PDGF‐BB on Smad1 expression; Smad1 overexpression partially reversed PDGF‐BB inhibited differentiation markers in VSMCs, while Smad1 knockdown partially rescued phenotypic changes in VSMCs in cells transfected with anti‐miR‐26a (Yang et al, ). Thus, it was confirmed that miR‐26a had a regulatory effect on PDGF‐BB‐mediated Smad1 expression in VSMCs.…”