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

Young, JA; Ting, KK; Li, J; Moller, T; Dunn, L; Lu, Y; Lay, AJ; Moses, J; Prado-Lourenço, L; Khachigian, LM; Ng, M; Gregory, PA; Goodall, GJ; Tsykin, A; Lichtenstein, I; Hahn, CN; Tran, N; Shackel, N; Kench, JG; McCaughan, G; Vadas, MA; Gamble, JR

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

Young, JA Ting, KK Li, J Moller, T Dunn, L Lu, Y Lay, AJ Moses, J Prado-Lourenço, L Khachigian, LM Ng, M Gregory, PA Goodall, GJ Tsykin, A Lichtenstein, I Hahn, CN Tran, N

Shackel, N Kench, JG McCaughan, G Vadas, MA Gamble, JR

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Publication Type:: Journal Article
Citation:: Blood, 2013, 122 (16), pp. 2911 - 2919
Issue Date:: 2013-01-01

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Field	Value	Language
dc.contributor.author	Young, JA	en_US
dc.contributor.author	Ting, KK	en_US
dc.contributor.author	Li, J	en_US
dc.contributor.author	Moller, T	en_US
dc.contributor.author	Dunn, L	en_US
dc.contributor.author	Lu, Y	en_US
dc.contributor.author	Lay, AJ	en_US
dc.contributor.author	Moses, J	en_US
dc.contributor.author	Prado-Lourenço, L	en_US
dc.contributor.author	Khachigian, LM	en_US
dc.contributor.author	Ng, M	en_US
dc.contributor.author	Gregory, PA	en_US
dc.contributor.author	Goodall, GJ	en_US
dc.contributor.author	Tsykin, A	en_US
dc.contributor.author	Lichtenstein, I	en_US
dc.contributor.author	Hahn, CN	en_US
dc.contributor.author	Tran, N https://orcid.org/0000-0001-7747-2530	en_US
dc.contributor.author	Shackel, N	en_US
dc.contributor.author	Kench, JG	en_US
dc.contributor.author	McCaughan, G	en_US
dc.contributor.author	Vadas, MA	en_US
dc.contributor.author	Gamble, JR	en_US
dc.date.issued	2013-01-01	en_US
dc.identifier.citation	Blood, 2013, 122 (16), pp. 2911 - 2919	en_US
dc.identifier.issn	0006-4971	en_US
dc.identifier.uri	http://hdl.handle.net/10453/116007
dc.description.abstract	© 2013 by The American Society of Hematology. 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 inmice 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 themiR-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.	en_US
dc.relation.ispartof	Blood	en_US
dc.relation.isbasedon	10.1182/blood-2012-12-473017	en_US
dc.subject.classification	Immunology	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Liver Cirrhosis	en_US
dc.subject.mesh	Ischemia	en_US
dc.subject.mesh	Neovascularization, Pathologic	en_US
dc.subject.mesh	Edema	en_US
dc.subject.mesh	Cadherins	en_US
dc.subject.mesh	MicroRNAs	en_US
dc.subject.mesh	Antigens, CD	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Binding Sites	en_US
dc.subject.mesh	Capillary Permeability	en_US
dc.subject.mesh	HEK293 Cells	en_US
dc.subject.mesh	Human Umbilical Vein Endothelial Cells	en_US
dc.title	Regulation of vascular leak and recovery from ischemic injury by general and VE-cadherin-restricted miRNA antagonists of miR-27	en_US
dc.type	Journal Article
utslib.citation.volume	16	en_US
utslib.citation.volume	122	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	en_US
utslib.for	1114 Paediatrics and Reproductive Medicine	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	16	en_US
pubs.publication-status	Published	en_US
pubs.volume	122	en_US

Abstract:

© 2013 by The American Society of Hematology. 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 inmice 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 themiR-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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/116007