Regulation of vascular leak and recovery from ischemic 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, Angelina J. Lay, 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 McCaughanMathew A. Vadas, Jennifer R. Gamble

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)


Cellular junctions are essential to the normal functioning of the endothelium and control angiogenesis, tissue leak, and inflammation. From a screen of micro RNAs (miRNAs) altered in in vitro angiogenesis, we selected a subset predicted to target junctional molecules. MiR-27a was rapidly downregulated upon stimulation of in vitro angiogenesis, and its level of expression is reduced in neovessels in vivo. The downregulation of miR-27a was essential for angiogenesis because 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 vascular endothelial growth factor 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 edema, 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.

Original languageEnglish
Pages (from-to)2911-2919
Number of pages9
Issue number16
Publication statusPublished - 17 Oct 2013
Externally publishedYes

Bibliographical note

An erratum exists for this article and can be found in Blood (2012) Vol 122(19) p. 3034, at doi: 10.1182/blood-2014-09-604066


  • Animals
  • Antigens, CD/metabolism
  • Binding Sites
  • Cadherins/metabolism
  • Capillary Permeability
  • Edema/pathology
  • Gene Expression Regulation
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Ischemia/pathology
  • Liver Cirrhosis/pathology
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs/antagonists & inhibitors
  • Neovascularization, Pathologic


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