Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells. Correlation with the expression of specific endogenous growth factors and reversal by suramin.
By means of a rat aortic smooth muscle (RASM) cell culture model, the effects of angiotensin II (AII) on early proto-oncogene gene expression, DNA synthesis, and cell proliferation were measured and compared to known mitogens. In 24-h [3H]-thymidine incorporation assays, AII was found to be a weak mitogen when compared to potent mitogens such as fetal bovine serum and platelet-derived growth factor (PDGF). In contrast, when assays were carried out for 48 h, AII induced a significant dose-dependent stimulation of DNA synthesis, which more than doubled at 3 nM AII, and was maximal (five- to eightfold above control) at 100 nM AII. Treatment of cells with the AII type 1 receptor antagonist losartan inhibited the mitogenic effects of AII. AII also stimulated smooth muscle cell proliferation, as indicated by an absolute increase in cell number after AII stimulation of RASM cells for 5 d. AII stimulation of RASM cell growth correlated with the increased expression of specific endogenous growth factors, including transforming growth factor beta 1 (TGF-beta 1) and PDGF A-chain. However, addition of either PDGF- or TGF-beta 1-neutralizing antibodies failed to significantly reduce the delayed mitogenic effects induced by AII. In contrast, we found that AII-stimulated mitogenesis could be inhibited in a dose-dependent manner by the growth factor inhibitor drug suramin. Taken together, our results indicate that enhanced endogenous growth factor expression may represent the direct mechanism by which AII promotes smooth muscle cell growth in some vascular hyperproliferative diseases.
Weber
H
H
Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543.
Taylor
D S
DS
Molloy
C J
CJ
D016475:3T3 Cells; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000077214:Becaplermin; D002455:Cell Division / Q000187:drug effects*; D017077:Culture Media, Conditioned; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D016762:Genes, fos / Q000187:drug effects; D006133:Growth Substances / Q000096:biosynthesis* / Q000276:immunology; D007700:Kinetics; D051379:Mice; D008934:Mitogens / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D019000:Phosphotyrosine; D010982:Platelet-Derived Growth Factor / Q000276:immunology / Q000494:pharmacology / Q000502:physiology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013498:Suramin / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000906:Antibodies; D017077:Culture Media, Conditioned; D006133:Growth Substances; D008934:Mitogens; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; C075278:platelet-derived growth factor A; D000804:Angiotensin II; D000077214:Becaplermin; D019000:Phosphotyrosine; D014443:Tyrosine; D013498:Suramin; D004247:DNA; D013936:Thymidine