Background Chronic inflammatory or proliferative stimuli, e.g., a lasting exposure to increased growth factor levels, cause vascular smooth muscle cells (SMC) to switch from a contractile phenotype towards a synthetic and proliferative phenotype, a phenomenon with a huge impact on the development of atherosclerosis. The molecular events leading to this phenotype change are not well understood. Methods Human cultured thymus vein SMC (passage 2-4) were exposed to platelet-derived growth factor (PDGF; 60 U/mL). Gene and protein expression of various PDGF-sensitive gene products and the transcriptional repressor ZFM1 were analysed by real time RT-PCR, Western blot analysis and immunofluorescence analysis, respectively. Molecular mechanisms of zfm1 gene expression were analysed by reporter gene analysis, gel shift assays and chromosome immuno- precipitation analyses. Results Exposure of SMC to PDGF leads to proliferation and increased expression of several gene products. Interestingly, expression of the ZFM1 is suppressed by a novel mechanism: the very fast PDGF-induced expression of the transcription factor early growth response-1 (EGR-1) causes a physical displacement of another transcription factor, SP1, from two canonical binding sites around position -180 of the zfm1 gene promoter, efficiently abrogating the transcription of the gene. This EGR-1- mediated suppression of ZFM1 expression is a prerequisite for PDGF-induced gene expression and proliferation in SMC. Consequently, siRNA- induced ZFM1 knock down (5 mg/well for 72 h) alone is sufficient to increase proliferation and expression of PDGF-sensitive gene products. Conversely, over-expression of (GFP-tagged) ZFM1 effectively suppresses all PDGF-induced effects analysed here. Conclusions ZFM1 expression levels pivotally determine the SMC phenotype: Whereas its down- regulation is necessary for PDGF-induced changes, the maintenance of ZFM1 expression is sufficient to maintain contractile SMC phenotype.