Regulation of vascular contractility and blood pressure by the E2F2 transcription factor.
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.
Zhou
Junlan
J
Assistant Professor, Feinberg Cardiovascular Research Institute, Northwestern University, 303 E Chicago Ave, Tarry 14-751, Chicago, IL 60611, USA.
Zhu
Yan
Y
Cheng
Min
M
Dinesh
Deepika
D
Thorne
Tina
T
Poh
Kian Keong
KK
Liu
Dongxu
D
Botros
Chantal
C
Tang
Yao Liang
YL
Reisdorph
Nichole
N
Kishore
Raj
R
Losordo
Douglas W
DW
Qin
Gangjian
G
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*
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