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.
ASJC Scopus subject areas