Regulated expression of the platelet-derived growth factor A chain gene in microvascular endothelial cells.
Platelet-derived growth factor (PDGF) is composed of homologous polypeptide chains, termed A and B, that are expressed as mitogenically active A-A, B-B, or A-B dimers. Previous work in our laboratory has demonstrated that PDGF B chain mRNA expression is stimulated in microvascular endothelial cells by phorbol esters (PMA), thrombin, and transforming growth factor-beta (TGF-beta) and blocked by agents that elevate cyclic AMP (cAMP). Here we report the first evidence that the expression of A chain mRNA is also regulated in these cells. PDGF A chain mRNA levels were increased 5-25-fold by phorbol esters, thrombin, and TGF-beta. Transcripts of four different sizes were induced. The increase in A chain mRNA stimulated by TGF-beta was more prolonged (peak 4 h, duration 48 h) than the increase stimulated by PMA and thrombin (peak 4 h, duration 8 h). Among the agents known to increase B chain mRNA levels, PMA was most efficacious, followed in decreasing order by thrombin and TGF-beta. However, for A chain mRNA induction by these same agents, the order was reversed; TGF-beta was most efficacious, followed in decreasing order by thrombin and PMA. Agents that elevate cyclic AMP, known to block induction of B chain mRNA, blocked A chain induction by thrombin but had less effect on A chain mRNA induced by TGF-beta. Thus PDGF A chain mRNA levels are regulated by the same agents that regulate B chain mRNA levels in microvascular endothelial cells. While the changes in A chain mRNA are qualitatively similar to the changes in B chain mRNA in microvascular endothelial cells, there are differences in the relative efficacies of these agents in the regulation of PDGF A and B chain genes. These differences suggest that the forms of PDGF produced by endothelial cells depend on the nature of the inducing stimulus.
D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D010455:Peptides / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D015291:Transforming Growth Factors
D010455:Peptides; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D005576:Colforsin; D015291:Transforming Growth Factors; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate