The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells.

The molecular mechanisms regulating endothelial cell activation and vascular smooth muscle cell proliferation are critical in the pathological processes underlying atherosclerosis. Numerous growth factors and cytokines trigger the complex and redundant signaling pathways that regulate cell cycle entry; however, the genes controlling these processes are not fully known. Applying techniques for differential gene expression analysis, new transcription factors have been identified in these mechanisms, among them the three members of the NR4A subfamily of nuclear receptors (NRs). These transcription factors (NOR-1, Nur77 and Nurr1) are products of immediate-early genes whose expression and activity is regulated in a cell-specific manner by a variety of extracellular mitogenic, apoptotic and differentiation stimuli. Unlike most NRs whose transcriptional activity is regulated by direct modulatory ligands, NR4A genes do not appear to require ligand binding for activation, and in vascular cells they are highly responsive to growth factors, cytokines, lipoproteins and thrombin. In this review, we discuss our present knowledge on the role of this subfamily of NRs in vascular cell function.