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

Overview

MeSH

  • Androstadienes
  • Apoptosis
  • Cells, Cultured
  • Chromones
  • Enzyme Inhibitors
  • Genetic Vectors
  • Humans
  • Morpholines
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt

MeSH Major

  • 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.

publication date

  • March 19, 2004

has subject area

  • Adenovirus E4 Proteins
  • Androstadienes
  • Apoptosis
  • Cadherins
  • Cell Survival
  • Cells, Cultured
  • Chromones
  • Endothelium, Vascular
  • Enzyme Inhibitors
  • Genetic Vectors
  • Humans
  • Morpholines
  • Neovascularization, Physiologic
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1074/jbc.M312221200

PubMed ID

  • 14660586

Additional Document Info

start page

  • 11760

end page

  • 11766

volume

  • 279

number

  • 12