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J. Biol. Chem., Vol. 283, Issue 23, 15878-15883, June 6, 2008

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MicroRNA-210 Modulates Endothelial Cell Response to Hypoxia and Inhibits the Receptor Tyrosine Kinase Ligand Ephrin-A3^*

Pasquale Fasanaro, Yuri D'Alessandra, Valeria Di Stefano^¶, Roberta Melchionna, Sveva Romani, Giulio Pompilio, Maurizio C. Capogrossi, and Fabio Martelli¹

From the Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, IRCCS, 00167 Rome, the Laboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino, IRCCS, 20138 Milan, and the ^¶Laboratorio di Cardiologia Molecolare, Policlinico San Donato, IRCCS, 20097 Milan, Italy

MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as negative gene expression regulators. In the present study, we investigated miRNAs role in endothelial cell response to hypoxia. We found that the expression of miR-210 progressively increased upon exposure to hypoxia. miR-210 overexpression in normoxic endothelial cells stimulated the formation of capillary-like structures on Matrigel and vascular endothelial growth factor-driven cell migration. Conversely, miR-210 blockade via anti-miRNA transfection inhibited the formation of capillary-like structures stimulated by hypoxia and decreased cell migration in response to vascular endothelial growth factor. miR-210 overexpression did not affect endothelial cell growth in both normoxia and hypoxia. However, anti-miR-210 transfection inhibited cell growth and induced apoptosis, in both normoxia and hypoxia. We determined that one relevant target of miR-210 in hypoxia was Ephrin-A3 since miR-210 was necessary and sufficient to down-modulate its expression. Moreover, luciferase reporter assays showed that Ephrin-A3 was a direct target of miR-210. Ephrin-A3 modulation by miR-210 had significant functional consequences; indeed, the expression of an Ephrin-A3 allele that is not targeted by miR-210 prevented miR-210-mediated stimulation of both tubulogenesis and chemotaxis. We conclude that miR-210 up-regulation is a crucial element of endothelial cell response to hypoxia, affecting cell survival, migration, and differentiation.

Received for publication, January 28, 2008 , and in revised form, April 15, 2008.

^* This work was supported by the Ministero della Salute (Grants RC06/07-1.13, RF05-Conv.79.1, RF05-ISS 64D/F4, RF06-Conv.74.1; RF07Onc-26/1; and RO.06-M.-conv.29/07-1). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text, three supplemental tables, and eight supplemental figures.

¹ To whom correspondence should be addressed. Tel.: 39-06-6646-2431; Fax: 39-06-6646-2430; E-mail: f.martelli{at}idi.it.

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