Abstract 443: Transcription Factor E2F2 Regulates Vessel Contractile Function and Blood Pressure via Isoform-specific Expressions of Endothelin Converting Enzyme-1
E2F transcription factors play critical roles in cell cycle regulation but their cardiovascular specific functions are not well defined. Recent studies have revealed a polymorphism in Endothelin Converting Enzyme-1b (ECE-1b) promoter (C-338A), located within E2F consensus site, which is strongly associated with blood pressure (BP) values in hypertensive women. ECE-1, with four isoforms ECE-1a/b/c/d expressed by the use of alternative promoters, is the major enzyme that catalyzes the biogenesis of the potent vessel-constricting peptide endothelin-1 (ET-1) from its inactive precursor Big-ET-1. The role of E2Fs in ECE-1 bioactivity and BP regulation, however, is unknown. Here we provide evidence that E2F2- but not E2F1-deficient mice display an elevated arterial BP. Loss of E2F2 leads to an aortic artery hypercontractility in response to Big-ET-1, indicating an increased ECE-1 bioactivity. ECE-1b promoter-reporter assays, combined with either E2F2 overexpression or knockdown, confirm that E2F2 regulates ECE-1b transcription. The incorporation of C-338A polymorphism in the promoter confers a higher basal level of the promoter activity and blunts the induction of ECE-1b by E2F2. Among all four isoforms, ECE-1b has been suggested to localize in the late endosome and heterodimerize with cell surface ECE-1a/c/d isoforms for lysosomal degradation, thereby down-regulating their activities. Indeed, we found that knockdown of E2F2 leads to a reduced cytosolic however an increased plasma membrane ECE-1 immunoactivity, corroborating with the hypercontractility of E2F2-deficient vessels. These data indicate that in the normal “non-proliferating” vessels, E2F2 plays a critical role in the maintenance of vascular tone. Deregulated E2F2 activity may contribute to the pathogenesis of hypertension.