Abstract
Bach1 disrupts Wnt/β-catenin signaling, reduces the proliferation, migration, and tube formation activity of endothelial cells (ECs), and suppresses angiogenesis in mice with surgically induced hind-limb ischemia (HLI). However, the function of Bach1 during developmental angiogenesis in zebrafish remains unclear. Here, we found that zebrafish Bach1 was expressed ubiquitously during early embryonic development in zebrafish. Bach1b mRNA injection of Tg(fli1:gfp) fish disrupted intersegmental vessels (ISV) and dorsal longitudinal anastomotic vessels (DLAV) and suppressed endogenous Wnt/β-catenin signaling and Wnt8a stimulated vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) gene expression at early embryonic stages of zebrafish. Furthermore, chromatin immunoprecipitation experiments confirmed that Bach1 occupied the TCF/LEF-binding site of the VEGF promoter in human umbilical vein endothelial cells (HUVECs). Bach1 inhibited VEGF transcription by recruiting histone deacetylase 1 (HDAC1) to the VEGF promoter in HUVECs. Exogenous administration of VEGF or IL-8 partially rescued Bach1-driven antiangiogenic functions in HUVECs. Taken together, these observations indicate that Bach1 suppresses the developmental angiogenesis of zebrafish and that this function is associated with declines in Wnt/β-catenin signaling and VEGF and IL-8 expression.
Highlights
Wnt signaling has been implicated in cardiovascular development, including placental vascular development, endothelial cell fate specification and endothelial cell proliferation, and vascular growth and integrity [1,2,3]
We have shown that BTB and CNC homology 1 (Bach1) binds to TCF4, reduces the interaction of β-catenin with TCF4, and disrupts Wnt/β-catenin signaling by recruiting histone deacetylase 1 to the promoter of TCF4-targeted genes [14]
Our results indicate that Bach1 reduces the proliferation, migration, and tube formation activity of human endothelial cells (ECs), induces endothelial cell apoptosis and cell-cycle arrest, and suppresses angiogenesis in mice with surgically induced hind-limb ischemia (HLI) [14, 15]
Summary
Wnt signaling has been implicated in cardiovascular development, including placental vascular development, endothelial cell fate specification and endothelial cell proliferation, and vascular growth and integrity [1,2,3]. Wnt signaling is reported to promote expressions of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) [6, 7], which have been shown to have angiogenic activity in human endothelial cells and zebrafish [8,9,10,11]. Our results indicate that Bach reduces the proliferation, migration, and tube formation activity of human endothelial cells (ECs), induces endothelial cell apoptosis and cell-cycle arrest, and suppresses angiogenesis in mice with surgically induced hind-limb ischemia (HLI) [14, 15]. These observations suggest Bach as a major regulator of endothelial function and ischemia-induced angiogenesis. Little is yet known about the role of Bach in vascular development
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