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J. Biol. Chem., Vol. 280, Issue 15, 14790-14798, April 15, 2005

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Telomerase Mediates Vascular Endothelial Growth Factor-dependent Responsiveness in a Rat Model of Hind Limb Ischemia^*

Germana Zaccagnini, Carlo Gaetano¶, Linda Della Pietra||, Simona Nanni||**, Annalisa Grasselli||, Antonella Mangoni, Roberta Benvenuto¶, Manuela Fabrizi¶, Silvia Truffa¶, Antonia Germani, Fabiola Moretti||, Alfredo Pontecorvi||, Ada Sacchi||, Silvia Bacchetti||, Maurizio C. Capogrossi¶, and Antonella Farsetti||¶¶

From the Laboratory of Vascular Biology and Gene Therapy, Cardiology Center "I. Monzino," Milan 20138, Italy, ^¶Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata, Rome 00167, Italy, ^||Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Regina Elena Institute-Centro Ricerca Sperimentali, Rome 00158, Italy, Institute of Medical Pathology, Catholic University, Rome 00168, Italy, and Institute of Neurobiology and Molecular Medicine, National Research Council, Rome 00137, Italy

Telomere dysfunction contributes to reduced cell viability, altered differentiation, and impaired regenerative/proliferative responses. Recent advances indicate that telomerase activity confers a pro-angiogenic phenotype to endothelial cells and their precursors. We have investigated whether telomerase contributes to tissue regeneration following hind limb ischemia and vascular endothelial growth factor 165 (VEGF₁₆₅) treatment. VEGF delivery induced angiogenesis and increased expression of the telomerase reverse transcriptase (TERT) and telomerase activity in skeletal muscles and satellite and endothelial cells. Adenovirus-mediated transfer of wild type TERT but not of a dominant negative mutant, TERTdn, significantly induced capillary but not arteriole formation. However, when co-delivered with VEGF, TERTdn abrogated VEGF-dependent angiogenesis, arteriogenesis, and blood flow increase. This effect was paralleled by in vitro evidence that telomerase inhibition by 3'-azido-3'-deoxythymidine in VEGF-treated endothelial cells strongly reduced capillary density and promoted apoptosis in the absence of serum. Similar results were obtained with adenovirus-mediated expression of TERTdn and AKTdn, both reducing endogenous TERT activity and angiogenesis on Matrigel. Mechanistically, neo-angiogenesis in our system involved: (i) VEGF-dependent activation of telomerase through the nitric oxide pathway and (ii) telomerase-dependent activation of endothelial cell differentiation and protection from apoptosis. Furthermore, detection of TERT in activated satellite cells identified them as VEGF targets during muscle regeneration. Because TERT behaves as an angiogenic factor and a downstream effector of VEGF signaling, telomerase activity appears required for VEGF-dependent remodeling of ischemic tissue at the capillaries and arterioles level.

Received for publication, December 29, 2004

^* This work was supported in part by grants of Ministero della Salute (to M. C. C., A. F., and C. G.), Associazione Italiana per la Ricerca sul Cancro (to A. F., and C. G.), and Progetto Strategico MIUR-CNR (Legge 449/97). 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.

Both authors contributed equally to this work.

^** Supported by Federazione Italiana Ricerca sul Cancro fellowship.

^¶¶ To whom correspondence should be addressed: Dept. of Experimental Oncology, Molecular Oncogenesis, Regina Elena Institute-CRS, Via delle Messi d'Oro 156, 00158 Roma, Italy. Tel.: 39-0652662531; Fax: 39-064180526; E-mail: farsetti{at}ifo.it.

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