XBP1 splicing triggers miR-150 transfer from smooth muscle cells to endothelial cells via extracellular vesicles.

Yue Zhao,Qingbo Xu,Lingfang Zeng,Junyao Yang,Yi Li,Yanhua Hu,Tong Li,Ka-Hou Lao,Gillian Cockerill,Gang Wang,Peiyi Luo,Yingtang Gao

doi:10.1038/srep28627

Yue Zhao, Qingbo Xu + Show 10 more

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https://doi.org/10.1038/srep28627

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The interaction between endothelial cells (ECs) and smooth muscle cells (SMCs) plays a critical role in the maintenance of vessel wall homeostasis. The X-box binding protein 1 (XBP1) plays an important role in EC and SMC cellular functions. However, whether XBP1 is involved in EC-SMC interaction remains unclear. In this study, In vivo experiments with hindlimb ischemia models revealed that XBP1 deficiency in SMCs significantly attenuated angiogenesis in ischemic tissues, therefore retarded the foot blood perfusion recovery. In vitro studies indicated that either overexpression of the spliced XBP1 or treatment with platelet derived growth factor-BB up-regulated miR-150 expression and secretion via extracellular vesicles (EVs). The XBP1 splicing-mediated up-regulation of miR-150 might be due to increased stability. The SMC-derived EVs could trigger EC migration, which was abolished by miR-150 knockdown in SMCs, suggesting miR-150 is responsible for SMC-stimulated EC migration. The SMC-derived miR-150-containing EVs or premiR-150 transfection increased vascular endothelial growth factor (VEGF)-A mRNA and secretion in ECs. Both inhibitors SU5416 and LY294002 attenuated EVs-induced EC migration. This study demonstrates that XBP1 splicing in SMCs can control EC migration via SMC derived EVs-mediated miR-150 transfer and miR-150-driven VEGF-A/VEGFR/PI3K/Akt pathway activation, thereby modulating the maintenance of vessel wall homeostasis.

Highlights

The X-box binding protein 1 (XBP1) was originally identified as a stress-inducible transcription factor essential for cell survival under stress conditions[18,19,20]
Our study revealed that XBP1 splicing was activated in vascular SMCs in response to vascular injury in vivo and platelet derived growth factor-BB (PDGF-BB) stimulation in vitro and that XBP1 deficiency in SMCs attenuated neointima formation in mouse model of femoral artery injury[17]
These results suggest XBP1 deficiency in SMCs may affect angiogenesis, causing the retardation of the foot blood perfusion recovery

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Introduction

The X-box binding protein 1 (XBP1) was originally identified as a stress-inducible transcription factor essential for cell survival under stress conditions[18,19,20]. Our recent studies and reports from other groups showed that physiological stimuli like vascular endothelial cell growth factor (VEGF) could trigger XBP1 splicing in an ER stress response independent manner[22,23,24,25]. In ECs, XBP1 splicing plays diverse roles including cell proliferation[23], autophagy response[26] and apoptosis[27]. In SMCs, BMP-2 was reported to activate XBP1 splicing[28]. Our study revealed that XBP1 splicing was activated in vascular SMCs in response to vascular injury in vivo and platelet derived growth factor-BB (PDGF-BB) stimulation in vitro and that XBP1 deficiency in SMCs attenuated neointima formation in mouse model of femoral artery injury[17]. We demonstrated that XBP1 splicing in SMC regulated EC migration via EVs-mediated miR-150 transfer

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