Regulation of vascular smooth muscle cell proliferation role of NF-κΒ revisited

The transcription factor NF-kappa B regulates cell cycle progression and proliferation in a number of cell types. An important unresolved issue is the potential role of NF-kappa B in the proliferation of vascular smooth muscle cells (VSMCs) as a basis for the development of vascular disease. To investigate the contribution of NF-kappa B to mitogen-induced proliferation of VSMCs, a knock-in mouse model expressing the NF-kappa B superrepressor I kappa B alpha Delta N (c(I kappa B alpha Delta N)) was used. Comparing wild-type and I kappa B alpha Delta N-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-kappa B activation was not observed in VSMCs derived from transgenic mice expressing an NF-kappa B-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-kappa B activation. In contrast to VSMCs, mouse embryonic fibroblasts (MEFs) derived from I kappa B alpha Delta N-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(I kappa B alpha Delta N)) mice. These results implicate that essential pathogenetic functions of NF-kappa B 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-kappa B in the control of cellular proliferation.