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 Crystal, Shahin Rafii

Research output: Contribution to journalArticle

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Abstract

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-3α/β phosphorylation, β-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.

Original languageEnglish
Pages (from-to)11760-11766
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number12
DOIs
Publication statusPublished - 19 Mar 2004
Externally publishedYes

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Endothelial cells
Adenoviridae
Cell Survival
Endothelial Cells
Genes
Chemical activation
Phosphatidylinositol 3-Kinase
Phosphorylation
src-Family Kinases
Glycogen Synthase Kinase 3
Catenins
Capillary tubes
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Critical Pathways
JNK Mitogen-Activated Protein Kinases
Extracellular Signal-Regulated MAP Kinases
Caspase 3
Protein-Tyrosine Kinases
Cell Movement
cadherin 5

ASJC Scopus subject areas

  • Biochemistry

Cite this

Adenovirus E4 Gene Promotes Selective Endothelial Cell Survival and Angiogenesis via Activation of the Vascular Endothelial-Cadherin/Akt Signaling Pathway. / Zhang, Fan; Cheng, Joseph; Hackett, Neil R.; Lam, George; Shido, Koji; Pergolizzi, Robert; Jin, David K.; Crystal, Ronald; Rafii, Shahin.

In: Journal of Biological Chemistry, Vol. 279, No. 12, 19.03.2004, p. 11760-11766.

Research output: Contribution to journalArticle

Zhang, Fan ; Cheng, Joseph ; Hackett, Neil R. ; Lam, George ; Shido, Koji ; Pergolizzi, Robert ; Jin, David K. ; Crystal, Ronald ; Rafii, Shahin. / Adenovirus E4 Gene Promotes Selective Endothelial Cell Survival and Angiogenesis via Activation of the Vascular Endothelial-Cadherin/Akt Signaling Pathway. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 12. pp. 11760-11766.
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