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J. Biol. Chem., Vol. 279, Issue 12, 11760-11766, March 19, 2004

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Adenovirus E4 Gene Promotes Selective Endothelial Cell Survival and Angiogenesis via Activation of the Vascular Endothelial-Cadherin/Akt Signaling Pathway^*

Fan Zhang, Joseph Cheng¶, Neil R. Hackett||, George Lam¶, Koji Shido¶, Robert Pergolizzi||, David K. Jin¶, Ronald G. Crystal||, and Shahin Rafii¶**

From the Department of Genetic Medicine, the ^¶Division of Hematology and Oncology, and the ^||Belfer Gene Therapy Core Facility of Weill Medical College of Cornell University, New York, New York 10021

The early 4 region (E4) of the adenoviral vectors (AdE4⁺) prolongs human endothelial cell (EC) survival and alters the angiogenic response, although the mechanisms for the EC-specific, AdE4⁺-mediated effects remain unknown. We hypothesized that AdE4⁺ modulates EC survival through activation of the vascular endothelial (VE)-cadherin/Akt pathway. Here, we showed that AdE4⁺, but not AdE4^- vectors, selectively stimulated phosphorylation of both Akt at Ser⁴⁷³ and Src kinase in ECs. The phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin abrogated AdE4⁺ induction of both phospho-Akt expression and prolonged EC survival. Regulation of phospho-Akt was found to be under the control of various factors, namely VE-cadherin activation, Src kinase, tyrosine kinase, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Downstream targets of Akt signaling resulted in glycogen synthase kinase-3/ phosphorylation, -catenin up-regulation, and caspase-3 suppression, all of which led to AdE4⁺-mediated EC survival. Furthermore, infection with AdE4⁺ vectors increased the angiogenic potential of ECs by promoting EC migration and capillary tube formation in Matrigel plugs. This selective AdE4⁺-mediated enhanced motility of ECs was also blocked by PI3K inhibitors. Taken together, these results suggest that activation of the VE-cadherin/Akt pathway is critical for AdE4⁺-mediated survival of ECs and angiogenic potential.

Received for publication, November 7, 2003 , and in revised form, November 25, 2003.

^* This work was supported in part by National Institutes of Health P01 Grant HL59312 and by funds from GenVec, Inc., Gaithersburg, MD. 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.

Recipient of Programs of Excellence in Gene Therapy fellowships from NHLBI, National Institutes of Health.

^** Supported by NHLBI, National Institutes of Health R01 Grants HL61849, HL66592, HL67839, and HL59312, American Cancer Society Grant 101396, and a grant from the Leukemia and Lymphoma Society. To whom correspondence should be addressed: Dept. of Genetic Medicine, Division of Hematology-Oncology, Weill Medical College of Cornell University, 1300 York Ave., Rm. D601, New York, NY 10021. Tel.: 212-746-2070; Fax: 212-746-8866; E-mail: srafii{at}med.cornell.edu.

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