Abstract
ObjectiveIt has been shown that Mindbomb (Mib), an E3 Ubiquitin ligase, is an essential modulator of Notch signaling during development. However, its effects on vascular development remain largely unknown.Approaches and ResultsWe identified a number of novel proteins that physically interact with Mib, including the Factor Inhibiting Hypoxia Inducible Factor 1 (FIH-1, also known as HIF1AN) from a yeast two hybrid screen, as previously reported. In cultured cells, FIH-1 colocalizes with Mib1, corroborating their potential interaction. In zebrafish embryos, FIH-1 appears to modulate VEGF-A signaling activity; depletion of fih-1 induces ectopic expression of vascular endothelial growth factor–a (vegfa) and leads to exuberant ectopic sprouts from intersegmental vessels (ISVs). Conversely, over-expression of fih-1 substantially attenuates the formation of ISVs, which can be rescued by concurrent over-expression of vegfa, indicating that FIH-1/HIF1AN may fine tune VEGF-A signaling.ConclusionsTaken together, our data suggest that FIH-1 interacts with Mib E3 Ubiquitin ligase and modulates vascular development by attenuating VEGF-A signaling activity.
Highlights
During development, actively growing areas within embryos are exposed to hypoxic environments, and the vascular network undergoes a rapid expansion to accommodate an increasing demand of oxygen and nutrient supplies
Taken together, our data suggest that FIH-1 interacts with Mib E3 Ubiquitin ligase and modulates vascular development by attenuating Vascular Endothelial Growth Factor-A (VEGF-A) signaling activity
While VEGF-A serves as the main factor that promotes proliferation, migration, and survival of endothelial cells (ECs), additional factors are shown to provide an essential role during vascular development [4,5]
Summary
Actively growing areas within embryos are exposed to hypoxic environments, and the vascular network undergoes a rapid expansion to accommodate an increasing demand of oxygen and nutrient supplies. The vascular phenotype of mib2/2 embryos are more severe than those with compromised Notch signaling [12,18], suggesting that there may be additional factors that mediate Mib function during vascular development. Inhibition of FIH-1 in zebrafish embryos substantially increases ectopic angiogenic sprouts from the ISVs, while overexpression of FIH-1 causes severe disruption in ISVs, suggesting that FIH-1 functions as an anti-angiogenic factor during development. Considering that FIH-1 targets HIF1a, which induces the expression of VEGF-A [22,23], our data suggest that FIH-1 may function as a mediator linking the anti-angiogenic function of Mib to VEGF-A, and serve as an essential modifier of signaling during vascular development
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