Vegf signaling promotes vascular endothelial differentiation by modulating etv2 expression

Area of Science:

• Developmental biology
• Molecular biology
• Zebrafish models

Background:

• Vasculogenesis is crucial for embryonic development, forming blood vessels from mesoderm.
• Vascular Endothelial Growth Factor (Vegf) signaling is vital for vascular development, but its precise role in embryonic vasculogenesis is debated.
• Previous research suggested Vegf signaling influences arteriovenous specification or general endothelial differentiation.

Purpose of the Study:

• To elucidate the specific roles of Vegf signaling in embryonic vasculogenesis.
• To identify downstream targets of Vegf signaling during vascular development.
• To resolve conflicting previous findings on Vegf's function in arteriovenous specification versus endothelial differentiation.

Main Methods:

• Utilized zebrafish embryos with chemical inhibitors of Vegf receptor (Vegfr) signaling.
• Employed zebrafish genetic mutants for Vegf pathway components.
• Analyzed gene expression of arterial, venous, and pan-endothelial markers.
• Investigated the role of the ETS transcription factor etv2/etsrp.

Main Results:

• High Vegfr inhibition reduced overall vascular markers and caused endothelial cell apoptosis.
• Low Vegfr inhibition specifically blocked arterial specification, leaving venous markers largely unaffected.
• Vegf overexpression expanded arterial and pan-endothelial markers while downregulating venous markers.
• Vegf signaling modulates etv2 expression, which is crucial for endothelial differentiation.
• etv2 overexpression rescued vascular defects in Vegfr-inhibited embryos.
• Zebrafish vegfaa mutants showed downregulated arterial/pan-endothelial markers and expanded venous markers.

Conclusions:

• Vegf signaling exhibits dose-dependent effects on embryonic vasculogenesis.
• Low Vegf levels promote general endothelial differentiation and survival by upregulating etv2.
• High Vegf levels promote arterial specification and inhibit venous specification.
• A revised model clarifies Vegf's distinct roles in vascular development based on signaling levels.