title: Adenovirus E4 gene promotes selective endothelial cell survival and angiogenesis via activation of the vascular endothelial-cadherin/Akt signaling pathway.
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.
authors.affiliation: Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Joseph
authors.initials: J
authors.lastname: Cheng
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hackett
authors.forename: George
authors.initials: G
authors.lastname: Lam
authors.forename: Koji
authors.initials: K
authors.lastname: Shido
authors.forename: Robert
authors.initials: R
authors.lastname: Pergolizzi
authors.forename: David K
authors.initials: DK
authors.lastname: Jin
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D017504:Adenovirus E4 Proteins / Q000235:genetics*; D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D015820:Cadherins / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005822:Genetic Vectors; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D000077191:Wortmannin
chemical_list: D017504:Adenovirus E4 Proteins; D000730:Androstadienes; D015820:Cadherins; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin