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Type: Journal article
Title: Regulation of vascular leak and recovery from ischemic injury by general and VE-cadherin-restricted miRNA antagonists of miR-27
Author: Young, J.
Ting, K.
Li, J.
Moller, T.
Dunn, L.
Lu, Y.
Moses, J.
Prado-Lourenco, L.
Khachigian, L.
Ng, M.
Gregory, P.
Goodall, G.
Tsykin, A.
Lichtenstein, I.
Hahn, C.
Tran, N.
Shackel, N.
Kench, J.
McCaughan, G.
Vadas, M.
et al.
Citation: Blood, 2013; 122(16):2911-2919
Publisher: American Society of Hematology
Issue Date: 2013
ISSN: 0006-4971
Statement of
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
Abstract: 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.
Keywords: Animals
Mice, Inbred C57BL
Liver Cirrhosis
Neovascularization, Pathologic
Antigens, CD
Gene Expression Regulation
Binding Sites
Capillary Permeability
HEK293 Cells
Human Umbilical Vein Endothelial Cells
Description: Please see erratum at DOI: 10.1182/blood-2014-09-604066 The errors have been corrected in the online version, which now differs from the print version.
Rights: © 2013 by The American Society of Hematology
DOI: 10.1182/blood-2012-12-473017
Published version:
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