Regulation of vascular smooth muscle cell proliferation: role of NF-kappaB revisited.
The transcription factor NF-kappaB regulates cell cycle progression and proliferation in a number of cell types. An important unresolved issue is the potential role of NF-kappaB in the proliferation of vascular smooth muscle cells (VSMCs) as a basis for the development of vascular disease. To investigate the contribution of NF-kappaB to mitogen-induced proliferation of VSMCs, a knock-in mouse model expressing the NF-kappaB superrepressor IkappaBalphaDeltaN (c(IkappaBalphaDeltaN)) was used. Comparing wild-type and IkappaBalphaDeltaN-expressing VSMCs, we found that proliferation rates did not differ after mitogenic stimulation by platelet-derived growth-factor-BB (PDGF-BB) or serum. In line with this, NF-kappaB activation was not observed in VSMCs derived from transgenic mice expressing an NF-kappaB-dependent lacZ reporter (c((Igk)3conalacZ)). We further show, that classical mitogenic signaling pathways (namely mitogen-activated protein kinase [MAPK] and the phosphatidyl-inositol-3-OH-kinase [PI3K] pathways) control VSMC proliferation, but independently of NF-kappaB activation. In contrast to VSMCs, mouse embryonic fibroblasts (MEFs) derived from IkappaBalphaDeltaN-expressing mice showed significantly impaired proliferation rates after mitogenic stimulation. This was reflected by strongly impaired cyclin D1 expression in serum-stimulated MEFs derived from (c(IkappaBalphaDeltaN)) mice. These results implicate that essential pathogenetic functions of NF-kappaB in the development of atherosclerosis involve apoptotic and inflammatory signaling of VSMCs rather than proliferation. They further provide genetic evidence for a cell-type restricted requirement of NF-kappaB in the control of cellular proliferation.
Mehrhof
Felix B
FB
Medizinische Klinik mit Schwerpunkt Kardiologie, Universitätsklinikum Charité, Campus Virchow Klinikum, Berlin, Germany.
Schmidt-Ullrich
Ruth
R
Dietz
Rainer
R
Scheidereit
Claus
C
D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D017930:Genes, Reporter; D020672:I-kappa B Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D001616:beta-Galactosidase / Q000235:genetics
D020672:I-kappa B Proteins; D008934:Mitogens; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D019938:Cyclin D1; D000072000:NF-KappaB Inhibitor alpha; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D001616:beta-Galactosidase