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MicroRNA-126 modulates endothelial SDF-1 expression and mobilization of Sca-1+/Lin progenitor cells in ischaemia

Coen van Solingen, Hetty C. de Boer, Roel Bijkerk, Matthieu Monge, Annemarie M. van Oeveren-Rietdijk, Leonard Seghers, Margreet R. de Vries, Eric P. van der Veer, Paul H.A. Quax, Ton J. Rabelink, Anton Jan van Zonneveld
DOI: http://dx.doi.org/10.1093/cvr/cvr227 449-455 First published online: 19 August 2011

Abstract

Aims MicroRNA-126 (miR-126), which is enriched in endothelial cells, plays a role in angiogenesis. Based on the seed sequence, miR-126 can also be predicted to regulate vasculogenesis by modulating the endothelial expression of stromal cell-derived factor-1 (SDF-1).

Methods and results Using miR-reporter constructs, we first validated that miR-126 inhibits SDF-1 expression in endothelial cells in vitro. Next, we investigated the potential relevance of this observation with respect to the mobilization of progenitor cells. For this, we studied the migration of human CD34+ progenitor cells towards chemotactic factors present in endothelial cell-conditioned medium. Antagomir-induced silencing of miR-126 elevated SDF-1 expression by human umbilical vein endothelial cells and enhanced migration of the CD34+ cells. In a murine model of hind limb ischaemia, a striking increase in the number of circulating Sca-1+/Lin progenitor cells in antagomir-126-treated mice was observed when compared with scramblemir-treated controls. Immunohistochemical staining of capillaries in the post-ischaemic gastrocnemius muscle of miR-126-silenced mice revealed elevated SDF-1 expressing CD31-positive capillaries, whereas a mobilizing effect of miR-126 inhibition was not detected in healthy control animals.

Conclusion miR-126 can regulate the expression of SDF-1 in endothelial cells. In the context of an ischaemic event, systemic silencing of miR-126 leads to the mobilization of Sca-1+/Lin progenitor cells into the peripheral circulation, potentially in response to elevated SDF-1 expression by endothelial cells present in the ischaemic tissue.

  • MicroRNAs
  • Endothelial function
  • Ischaemia
  • Progenitor cells
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