Adenoviral gene transfer of PDGF downregulates gasgene product PDGFαR and prolongs ERK and Akt/PKB activation

Abstract

The delivery of platelet-derived growth factor (PDGF) for tissue engineering of skin and periodontal wounds has become an active area of interest. However, little is known regarding the extended effects of PDGF on cell signaling via gene therapy and how such an approach facilitates the exiting of cells from growth arrest and entry to competence required for cell cycling. We show in vitro expression and secretion of PDGF-AA by recombinant adenovirus encoding the PDGF-A gene (Ad-PDGF-A). The bioactive PDGF-AA protein released induces sustained downregulation of PDGFαR that is encoded by a growth arrest-specific ( gas) gene. Ad-PDGF-A induces sustained phosphorylation of PDGFαR as well as prolonged phosphorylation of downstream extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Furthermore, the phosphorylation of PDGFαR is abolished by cotransducing cells with adenovirus encoding a dominant negative mutant of the PDGF-A gene that disrupts PDGF bioactivity. These findings demonstrate the prolonged effects of adenoviral delivery of PDGF and aid in the better understanding of sustained PDGF signaling.