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Circulation

Year: 2009  |  Volume: 120  |  Issue: 13  |  Page No.: 1213 - 1221

Regulation of Vascular Contractility and Blood Pressure by the E2F2 Transcription Factor

J Zhou, Y Zhu, M Cheng, D Dinesh, T Thorne, K. K Poh, D Liu, C Botros, Y. L Tang, N Reisdorph, R Kishore, D. W Losordo and G. Qin

Abstract

Background— Recent studies have identified a polymorphism in the endothelin-converting enzyme (ECE)–1b promoter (–338C/A) that is strongly associated with hypertension in women. The polymorphism is located in a consensus binding sequence for the E2F family of transcription factors. E2F proteins are crucially involved in cell-cycle regulation, but their roles in cardiovascular function are poorly understood. Here, we investigated the potential role of E2F2 in blood pressure regulation.

Methods and Results— Tail-cuff measurements of systolic and diastolic blood pressures were significantly higher in E2F2-null (E2F2–/–) mice than in their wild-type littermates, and in ex vivo ring assays, aortas from the E2F2–/– mice exhibited significantly greater contractility in response to big endothelin-1. Big endothelin-1 is activated by ECE-1, and mRNA levels of ECE-1b, the repressive ECE-1 isoform, were significantly lower in E2F2–/– mice than in wild-type mice. In endothelial cells, chromatin immunoprecipitation assays confirmed that E2F2 binds the ECE-1b promoter, and promoter-reporter assays indicated that E2F2 activates ECE-1b transcription. Furthermore, loss or downregulation of E2F2 led to a decline in ECE-1b levels, to higher levels of the membranous ECE-1 isoforms (ie, ECE-1a, -1c, and -1d), and to deregulated ECE-1 activity. Finally, Sam68 coimmunoprecipitated with E2F2, occupied the ECE-1b promoter (chromatin immunoprecipitation), and repressed E2F2-mediated ECE-1b promoter activity (promoter-reporter assays).

Conclusion— Our results identify a cell-cycle–independent mechanism by which E2F2 regulates endothelial function, arterial contractility, and blood pressure.

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