Tyrphostin A9 and wortmannin perturb the Golgi complex and block proliferation of vascular smooth muscle cells.
To proliferate, vascular smooth muscle cells first convert from a contractile to a synthetic phenotype. Earlier studies indicate that this process is supported by fibronectin and accelerated by platelet-derived growth factor (PDGF). Here, the mechanisms in this transition were further explored. Isolated rat aortic smooth muscle cells were treated with tyrphostin A9, a PDGF receptor tyrosine kinase inhibitor, and wortmannin, a phosphoinositide 3-kinase inhibitor. Electron microscopy did not show any effect on the reorganization of the cells during the first days in culture, i.e. the loss of actin filaments and the formation of a large secretory apparatus. Conversely, both drugs caused hypertrophy of the Golgi complex, with large and partly vacuolized cisternal stacks. Nevertheless, a juxtanuclear staining pattern for the Golgi enzyme mannosidase II, the coat protein beta-COP, and the PDGF beta-receptor was retained. Moreover, the serum-induced proliferation of the cells was blocked. These findings suggest that signaling via PDGF receptor tyrosine kinases and phosphoinositide 3-kinases is not necessary for the shift of the smooth muscle cells from a contractile to a synthetic phenotype. On the other hand, these enzymes apparently carry out important functions in the control of intracellular membrane traffic and cell division.
Thyberg
J
J
Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006056:Golgi Apparatus / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology*; D010641:Phenotype; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor; D020032:Tyrphostins; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020032:Tyrphostins; C001784:SF 6847; C099852:PDGF receptor tyrosine kinase; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D000077191:Wortmannin