title: Regulation of vascular contractility and blood pressure by the E2F2 transcription factor.
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.
  
  
  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).
  
  
  CONCLUSIONS
  Our results identify a cell-cycle-independent mechanism by which E2F2 regulates endothelial function, arterial contractility, and blood pressure.
authors.affiliation: Assistant Professor, Feinberg Cardiovascular Research Institute, Northwestern University, 303 E Chicago Ave, Tarry 14-751, Chicago, IL 60611, USA.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Min
authors.initials: M
authors.lastname: Cheng
authors.forename: Deepika
authors.initials: D
authors.lastname: Dinesh
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Kian Keong
authors.initials: KK
authors.lastname: Poh
authors.forename: Dongxu
authors.initials: D
authors.lastname: Liu
authors.forename: Chantal
authors.initials: C
authors.lastname: Botros
authors.forename: Yao Liang
authors.initials: YL
authors.lastname: Tang
authors.forename: Nichole
authors.initials: N
authors.lastname: Reisdorph
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000502:physiology; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D050703:E2F2 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D005260:Female; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D011401:Promoter Regions, Genetic / Q000502:physiology; D016601:RNA-Binding Proteins / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050703:E2F2 Transcription Factor; C484940:E2f2 protein, mouse; D019332:Endothelin-1; C513253:Khdrbs1 protein, mouse; D016601:RNA-Binding Proteins; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes