The Synergistic Effect of PDGF-AA and IGF-1 on VSMC Proliferation Might Be Explained by the Differential Activation of Their Intracellular Signaling Pathways

Abstract As previous studies showed, PDGF-AA exerts a poor mitogenic effect on vascular smooth muscle cells. Simultaneous addition of insulin-like growth factor 1 (IGF-1), itself also poorly mitogenic, led to a significant increase in [ 3 H]thymidine incorporation into the cell DNA as well as a strong increase in cell number. To explain the synergistic effect of PDGF-AA and IGF-1 on VSMC proliferation, we describe the effects of the two growth factors on distinct intracellular signals: on the activation of the signal proteins mitogen-activated protein kinase (MAPK) isoforms p42 and p44 and on the protein kinase C (PKC) isoforms α, δ, and ϵ, and on the induction of the transcription factor c-fos. PDGF-AA strongly activated the MAPK isoforms and PKC δ as well as the induction of c-fos. In contrast, IGF-1 exerted no effect on the signals induced by PDGF-AA, but strongly activated PKC ϵ isoform. Comparing this signal pattern to the one of the mitogenically potent PDGF isoform PDGF-BB, we found that PDGF-BB activated all of the signal proteins investigated.