Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury

Jan Marcus Daniel, Daniela Penzkofer, Rebecca Teske, Jochen Dutzmann, Alexander Koch, Wiebke Bielenberg, Angelika Bonauer, Reinier A. Boon, Ariane Fischer, Johann Bauersachs, Eva Van Rooij, Stefanie Dimmeler, Daniel G. Sedding*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Aims MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, but the effects of miR-92a on re-endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific locked nucleic acid (LNA)-based antimiRs as well as endothelial- specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice. Methods and results MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin a5 and sirtuin1, and reduced eNOS expression in vitro. MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo, systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re-endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re-endothelialization, whereas no phenotypewas observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin a5 and sirtuin1. Conclusion Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.

Original languageEnglish
Pages (from-to)564-572
Number of pages9
JournalCardiovascular Research
Volume103
Issue number4
DOIs
Publication statusPublished - 1 Jan 2014

Cite this

Daniel, J. M., Penzkofer, D., Teske, R., Dutzmann, J., Koch, A., Bielenberg, W., ... Sedding, D. G. (2014). Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury. Cardiovascular Research, 103(4), 564-572. https://doi.org/10.1093/cvr/cvu162