Editors' ChoiceVascular Biology

A Step Closer to Therapy for Leaky Vessels.

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Science Translational Medicine  18 Sep 2013:
Vol. 5, Issue 203, pp. 203ec152
DOI: 10.1126/scitranslmed.3007553

The discovery that small RNAs can regulate gene expression earned the Nobel Prize for laureates A. Fire and C. Mellow and brought with it the potential to change the course of disease by silencing genes with small RNAs. A single short RNA sequence may regulate a large number of proteins, each with different properties. Nevertheless, these molecules are not yet used in the clinic .

Young et al. make a substantial advance toward this goal by elaborating the details of the action of a specific microRNA (miRNA) and finding a way to effectively block one of the targeted genes.

In their study of the endothelial cell junctional protein VE-cadherin, the authors used a miRNA microarray and prediction algorithms to identify miRNA-27 as a probable regulator of VE-cadherin. Then, they transfected endothelial cells with a miRNA-27 mimic and saw a decrease of VE-cadherin expression and localization, resulting in increased cell permeability and vascular leak. Complete knockdown of miRNA-27 with antibody to miRNA made of locked nucleic acids reversed the effect, even in the presence of stimuli that promote vessel leakiness such as thrombin, vascular endothelial growth factor, or vascular obstruction. Also, in an animal model of cirrhosis, expression of miRNA-27 was decreased, which is consistent with the angiogenic response associated with disease. In a first step toward therapy, targeted blockage of the miRNA-27 binding site with Blockmir CD5-2 boosted VE-cadherin and inhibited permeability to thrombin and to VEGF-induced vascular leak in mice. CD5-2 also helped to restore blood flow in a hind-limb ischemia mouse model.

Most important, CD5-2’s effect was specific to cadherin and did not alter protein expression of other miRNA-27 targets. Future work will reveal whether miRNA-27 targets can effectively regulate vascular permeability in vascular, inflammatory, and neoplastic diseases.

J. A. Young et al., Regulation of vascular leak and recovery from ischaemic injury by general and VE-cadherin-restricted miRNA antagonists of miR-27. Blood, published online 5 September 2013 (10.1182/blood-2012-12-473017). [Abstract]

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