Transcriptional regulation of smooth muscle phenotypic modulation

Phenotypic modulation of vascular smooth muscle cell plays a pivotal role in the development of vascular pathology, such as atherosclerosis and restenosis after angioplasty. We have identified the zinc finger protein BTEB2 as a DNA binding protein that regulates the nonmuscle myosin heavy chain (SMemb) promoter. BTEB2 is expressed in fetal aorta but not in adult aorta and is induced in the neointima in response to vascular injury. BTEB2 also activates a number of vascular disease-associated genes, such as tissue factor, PAI-1 (plasminogen activator inhibitor-1), and Egr-1 gene. We have further isolated and characterized the human BTEB2 gene. Functional studies using 5'-deletion and site-directed mutation constructs demonstrated that phorbol ester induces Egr-1, which can activate the BTEB2 promoter through binding to -32 from the transcription start site. These results suggest that phenotypic modulation of vascular smooth muscle cells occurring in response to mitogen stimulation may be mediated by BTEB2 through Egr-1 induction.