Effect of phenotype on the transcription of the genes for platelet-derived growth factor (PDGF) isoforms in human smooth muscle cells, monocyte-derived macrophages, and endothelial cells in vitro.
Proliferation of arterial smooth muscle cells (ASMCs) contributes considerably to enlargement of the arterial wall during atherosclerosis. The platelet-derived growth factor (PDGF) is a well-known mitogen and chemoattractant for ASMCs. Quantitative reverse transcription-polymerase chain reaction showed that cells appearing in atherosclerotic lesions, such as ASMCs, endothelial cells, and monocytes/macrophages, expressed mRNAs for both PDGF A and B chains in vitro, with the highest expression in endothelial cells. On proliferation, ASMCs and endothelial cells upregulated PDGF A mRNA. Differentiation of macrophages increased the amount of both mRNAs. Thus, the regulation of PDGF A- and B-chain expression depends on cell types and phenotypic states of the cells, which have also been found in vivo in human atherosclerotic lesions. PDGF A can be produced as short and long isoforms. The latter binds with high affinity to glycosaminoglycans. Irrespective of phenotype, only the minor part of total PDGF A mRNA consisted of the long variant in ASMCs, while endothelial cells produced 40% of total PDGF A as the long form. The differentiation of macrophages increased the production of the long PDGF A mRNA from 10% to 40%. Thus, increasing numbers of stimulated cells in the atherosclerotic lesion may increase the transcription of PDGF isoforms, and particularly of the long PDGF A isoform. Together with increasing amounts of ASMC-derived proteoglycans in developing lesions, this may contribute to accumulation of PDGF in the arterial wall matrix, resulting in prolonged stimulation of ASMCs.
Krettek
A
A
Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Sweden. alexandra.krettek@wlab.wall.gu.se
Fager
G
G
Lindmark
H
H
Simonson
C
C
Lustig
F
F
D000328:Adult; D000077214:Becaplermin; D002454:Cell Differentiation; D002633:Chemotaxis; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008970:Molecular Weight; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis; D012326:RNA Splicing; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic; D014680:Veins / Q000166:cytology
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C075278:platelet-derived growth factor A; D000077214:Becaplermin