Cellular dedifferentiation of endothelium is linked to activation and silencing of certain nuclear transcription factors: implications for endothelial dysfunction and vascular biology

We investigated the gene expression of the nuclear transcription factors c/ EBP alpha, GATA-2, and the silencer Oct-1 in conjunction with the gene expr ession of all major cytochrome P450 genes and of eNOS in cultures of endoth elial cells of the rat. The purity of cultured endothelial cells was also c onfirmed by flow cytometry measurements of PECAM-1, a surface antigen of en dothelial cells. Taken collectively, the gene expression and flow cytometry studies provide strong evidence for c/EBP alpha, GATA-2, and Oct-1 to play a key role in the cellular dedifferentiation of endothelial cells; gene ex pression of eight individual CYP genes in conjunction with protein activity could be significantly increased upon treatment with Aroclor 1254, a well- documented chemical inducer of a battery of genes. Nevertheless, the gene e xpression of c/EBP alpha, GATA-2, and most of the CW genes was dramatically reduced (up to 90%) in cell cultures lacking PECAM-1 expression; in strong contrast, expression of the silencer Oct-1 was massively increased (simila r to 14 fold). We thus conclude activation of the silencer Oct-1 to be stro ngly correlated with loss of PECAM-1 and eNOS gene expression, e.g., loss o f cellular differentiation and endothelial function; in conjunction, gene e xpression of all major P450 isoforms was dramatically reduced in cultures o f dedifferentiated endothelial cells. This process of cellular dedifferenti ation and endothelial dysfunction was accompanied by down-regulation of end othelial specific transcription factors.