The synergistic effect of PDGF-AA and IGF-1 on VSMC proliferation might be explained by the differential activation of their intracellular signaling pathways.
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 [3H]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 alpha, delta, and epsilon, and on the induction of the transcription factor c-fos. PDGF-AA strongly activated the MAPK isoforms and PKC delta 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 epsilon 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.
Thömmes
K B
KB
Medizinische Universitäts-Poliklinik, Wilhelmstr. 35-37, Bonn, 53111, Germany.
Hoppe
J
J
Vetter
H
H
Sachinidis
A
A
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000077214:Becaplermin; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007536:Isomerism; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects*; D013936:Thymidine / Q000378:metabolism; D014316:Tritium / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000925:Anticoagulants; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D016760:Proto-Oncogene Proteins c-fos; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C075278:platelet-derived growth factor A; D014316:Tritium; D000077214:Becaplermin; D007334:Insulin-Like Growth Factor I; D004247:DNA; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013936:Thymidine