Adenovirus E4 gene promotes selective endothelial cell survival and angiogenesis via activation of the vascular endothelial-cadherin/Akt signaling pathway.

Publication Type	Academic Article
Authors	Zhang F, Cheng J, Hackett N, Lam G, Shido K, Pergolizzi R, Jin D, Crystal R, Rafii S
Journal	J Biol Chem
Volume	279
Issue	12
Pagination	11760-6
Date Published	12/02/2003
ISSN	0021-9258
Keywords	Adenovirus E4 Proteins, Cadherins, Cell Survival, Endothelium, Vascular, Neovascularization, Physiologic, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Signal Transduction
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 Ser(473) 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-3alpha/beta phosphorylation, beta-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.
DOI	10.1074/jbc.M312221200
PubMed ID	14660586