title: Regulation of vascular leak and recovery from ischemic injury by general and VE-cadherin-restricted miRNA antagonists of miR-27.
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.
authors.affiliation: Centre for the Endothelium, Vascular Biology Program, Centenary Institute, and University of Sydney, Sydney, Australia;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Young
authors.forename: Ka Ka
authors.initials: KK
authors.lastname: Ting
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Thorleif
authors.initials: T
authors.lastname: Moller
authors.forename: Louise
authors.initials: L
authors.lastname: Dunn
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Joshua
authors.initials: J
authors.lastname: Moses
authors.forename: Leonel
authors.initials: L
authors.lastname: Prado-Lourenço
authors.forename: Levon M
authors.initials: LM
authors.lastname: Khachigian
authors.forename: Martin
authors.initials: M
authors.lastname: Ng
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gregory
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
authors.forename: Anna
authors.initials: A
authors.lastname: Tsykin
authors.forename: Ilana
authors.initials: I
authors.lastname: Lichtenstein
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Hahn
authors.forename: Nham
authors.initials: N
authors.lastname: Tran
authors.forename: Nicholas
authors.initials: N
authors.lastname: Shackel
authors.forename: James G
authors.initials: JG
authors.lastname: Kench
authors.forename: Geoffrey
authors.initials: G
authors.lastname: McCaughan
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Vadas
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gamble
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability; D004487:Edema / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007511:Ischemia / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D035683:MicroRNAs; D000099152:Cadherin 5; C531388:MIRN27 microRNA, human