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Regulation of vascular leak and recovery from ischaemic injury by general and VE-cadherin-restricted miRNA antagonists of miR-27

Jennifer A. Young, Ka Ka Ting, Jia Li, Thorleif Moller, Louise Dunn, Ying Lu, Joshua Moses, Leonel Prado-Lourenço, Levon M. Khachigian, Martin Ng, Philip A. Gregory, Gregory J. Goodall, Anna Tsykin, Ilana Lichtenstein, Christopher N. Hahn, Nham Tran, Nicholas Shackel, James G. Kench, Geoffrey McCaughan, Mathew A. Vadas and Jennifer R. Gamble
This article has an Erratum 124(19):3034

Key points

  • Blockmirs are designed against the miR-27 binding site in VE-cadherin and display restricted specificity

  • MiRNA-27 and Blockmirs regulates VE-cadherin, and EC junctions, inhibit oedema, promote angiogenesis associated with ischaemia

Abstract

Cellular junctions are essential to the normal functioning of the endothelium and control angiogenesis, tissue leak and inflammation. From a screen of miRNAs altered in in vitro angiogenesis we selected a subset that are predicted to target junctional molecules. MiR-27a was rapidly downregulated upon stimulation of in vitro angiogenesis and its level of expression is reduced in neo-vessels in vivo. The downregulation of miR-27a was essential for angiogenesis since ectopic expression of miR-27a blocked capillary tube formation and angiogenesis. MiR-27a targets the junctional, endothelial specific cadherin, VE-cadherin. Consistent with this, vascular permeability to VEGF in mice is reduced by administration of a general miR-27 inhibitor. To determine that VE-cadherin was the dominant target of miR-27a function we used a novel technology with "Blockmirs", inhibitors that bind to the miR-27 binding site in VE-cadherin. The Blockmir CD5-2 demonstrated specificity for VE-cadherin and inhibited vascular leak in vitro and in vivo. Furthermore CD5-2 reduced oedema, increased capillary density and potently enhanced recovery from ischemic limb injury in mice. The Blockmir technology offers a refinement in the use of miRNAs especially for therapy. Further, targeting of endothelial junctional molecules by miRNAs has clinical potential especially in diseases associated with vascular leak.

  • Submitted December 17, 2012.
  • Accepted August 17, 2013.