Bach1 Represses Wnt/β-Catenin Signaling and Angiogenesis
Rationale: Wnt/β-catenin signaling has an important role in the angiogenic activity of endothelial cells (ECs). Bach1 is a transcription factor and is expressed in ECs, but whether Bach1 regulates angiogenesis is unknown.
Objective: This study evaluated the role of Bach1 in angiogenesis and Wnt/β-catenin signaling.
Methods and Results: Hind-limb ischemia (HLI) was surgically induced in Bach1-/- mice and their WT littermates and in C57BL/6J mice treated with adenoviruses coding for Bach1 or GFP. Lack of Bach1 expression was associated with significant increases in perfusion and vascular density and in the expression of pro-angiogenic cytokines in the ischemic hindlimb of mice, with enhancement of the angiogenic activity of ECs (e.g., tube formation, migration, and proliferation). Bach1 overexpression impaired angiogenesis in mice with HLI, and inhibited Wnt3a-stimulated angiogenic response and the expression of Wnt/β-catenin target genes, such as interleukin 8 (IL-8) and VEGF, in human umbilical vein endothelial cells (HUVECs). IL-8 and VEGF were responsible for the anti-angiogenic response of Bach1. Immunoprecipitation and GST pull-down assessments indicated that Bach1 binds directly to TCF4 and reduces the interaction of β-catenin with TCF4. Bach1 overexpression reduces the interaction between p300/CBP and β-catenin, as well as β-catenin acetylation, and chromatin immunoprecipitation experiments confirmed that Bach1 occupies the TCF4-binding site of the IL-8 promoter and recruits histone deacetylase 1 (HDAC1) to the IL-8 promoter in HUVECs.
Conclusions: Bach1 suppresses angiogenesis after ischemic injury and impairs Wnt/β-catenin signaling by disrupting the interaction between β-catenin and TCF4 and by recruiting HDAC1 to the promoter of TCF4-targeted genes.
- transcription factor Bach1
- Wnt signaling
- cell signaling
- endothelial cell
- Received May 8, 2015.
- Revision received June 24, 2015.
- Accepted June 29, 2015.