Role of ZFM1 in smooth muscle cell phenotype regulation

Abstract

Vascular smooth muscle cells (SMC) can rapidly develop a synthetic phenotype in response to growth factors ‐ a phenomenon with major impact on atherosclerosis. Despite its clinical relevance little is known about the mechanisms of this potentially reversible process.Using primary human cultured SMC and platelet‐derived growth factor (PDGF; 60 U/mL) we here show that the transcriptional repressor ZFM1 is a phenotype‐stabilizing factor in these cells. Exposure of SMC to PDGF leads to proliferation and synthetic gene expression. Interestingly, PDGF causes a rapid repression of ZFM1 gene transcription through replacement of Sp1 from the ZFM1 gene promoter by the transcription factor early growth response‐1. The subsequent drop in ZFM1 abundance disinhibits both proliferation and gene expression and is a prerequisite for PDGF‐induced effects in SMC. Consequently, siRNA‐induced ZFM1 knock down alone is sufficient to increase proliferation and expression of PDGF‐sensitive gene products. Conversely, over‐expression of ZFM1 effectively suppresses all effects of PDGF exposure.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 a contractile SMC phenotype.