Nitric oxide selectively amplifies FGF-2-induced mitogenesis in primary rat aortic smooth muscle cells.
Fibroblast growth factor is present in blood vessels and is thought to play an important role in promoting vascular cell proliferation in vivo. In the current study, we show that three agents that activate the guanosine 3',5'-cyclic monophosphate (cGMP) system, including the nitric oxide-generating agents S-nitroso-N-acetylpenicillamine (SNAP) and 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1) as well as the stable cGMP analogue 8-bromo-cGMP, increased fibroblast growth factor-2 (FGF-2; basic fibroblast growth factor)-induced [3H]thymidine incorporation by severalfold in primary cultures of rat aortic smooth muscle cells. SNAP increased the efficacy, but not the potency, of FGF-2. The stimulatory effect of SNAP was selective for FGF-2-induced mitogenesis as shown by the lack of a significant effect on [3H]thymidine incorporation induced by several other growth factors. Consistent with thymidine incorporation experiments, SNAP amplified the increase of the cellular DNA content induced by FGF-2 as well as the proliferation of cells. A selective inhibitor of cGMP phosphodiesterases, zaprinast, potentiated the comitogenic effect of SNAP and its ability to increase cGMP levels, supporting the involvement of cGMP as second messenger. Consistent with previous results, and opposite to that found in primary and early subculture, SNAP decreased mitogen-induced [3H]thymidine incorporation in cells in later subculture. Because macrophage- and vascular smooth muscle-derived nitric oxide is likely to be present in relatively large concentrations after vascular injury, we speculate that endogenous nitric oxide may amplify the activity of FGF-2 in vivo.
Hassid
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A
Department of Physiology and Biophysics, University of Tennessee, Memphis 38163.
Arabshahi
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H
Bourcier
T
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Dhaunsi
G S
GS
Matthews
C
C
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004357:Drug Synergism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology; D008297:Male; D008934:Mitogens / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors
D006133:Growth Substances; D008934:Mitogens; D011688:Purinones; D016222:Fibroblast Growth Factor 2; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D004247:DNA; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D010396:Penicillamine; C011145:zaprinast; D006152:Cyclic GMP; D013936:Thymidine