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(Circulation Research. 2005;96:958.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Regulation of Vascular Smooth Muscle Cell Proliferation

Role of NF-B Revisited

Felix B. Mehrhof, Ruth Schmidt-Ullrich, Rainer Dietz, Claus Scheidereit

From the Medizinische Klinik mit Schwerpunkt Kardiologie (F.B.M., R.D.), Universitätsklinikum Charité, Campus Virchow Klinikum, Berlin; and Max-Delbrück-Centrum for Molecular Medicine (F.B.M., R.S.-U., R.D., C.S.), Berlin, Germany

Correspondence to Claus Scheidereit, Max-Delbrück-Centrum for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany. E-mail scheidereit{at}mdc-berlin.de

The transcription factor NF-B regulates cell cycle progression and proliferation in a number of cell types. An important unresolved issue is the potential role of NF-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-B to mitogen-induced proliferation of VSMCs, a knock-in mouse model expressing the NF-B superrepressor IBN (c^IBN) was used. Comparing wild-type and IBN-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-B activation was not observed in VSMCs derived from transgenic mice expressing an NF-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-B activation. In contrast to VSMCs, mouse embryonic fibroblasts (MEFs) derived from IBN-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^IBN) mice. These results implicate that essential pathogenetic functions of NF-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-B in the control of cellular proliferation.

Key Words: VSMC proliferation • atherosclerosis • NF-B • PI3K • MAPK

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