Endothelial Semaphorin 3fb regulates Vegf pathway-mediated angiogenic sprouting

Area of Science:

• Vascular biology
• Developmental biology
• Cell signaling

Background:

• Vessel growth involves integrating external signals with internal pathways for cell migration and morphogenesis.
• Vascular Endothelial Growth Factor (VEGF) signaling controls pro-angiogenic effects during sprouting for efficient vascular network formation.

Purpose of the Study:

• To investigate the crosstalk between VEGF signaling and Semaphorin 3fb (Sema3fb) in zebrafish angiogenesis.
• To elucidate the role of Sema3fb in regulating endothelial cell migration and vascular sprouting.

Main Methods:

• Analysis of sema3fb gene expression in zebrafish endothelial cells.
• Phenotypic characterization of sema3fb mutant zebrafish.
• Assessment of signaling pathway components including VEGF receptor 2 (Vegfr2), delta-like 4 (dll4), and soluble Fms Related Receptor Tyrosine Kinase 1 (sflt1).
• Evaluation of phospho-ERK staining and rescue experiments by reducing Vegfr2 kinase activity.

Main Results:

• sema3fb is expressed in actively sprouting vessels.
• Loss of sema3fb leads to stunted, wide intersegmental vessel artery sprouts with reduced migration speed and dysregulated actin assembly.
• sema3fb mutants exhibit altered expression of pro-angiogenic and anti-angiogenic factors and enhanced VEGF signaling.
• Reducing Vegfr2 kinase activity rescues the angiogenic sprouting defects in sema3fb mutants.

Conclusions:

• Sema3fb acts as an autocrine cue that modulates intrinsic growth factor signaling, particularly the VEGF pathway.
• Sema3fb is critical for promoting endothelial sprouting and ensuring proper vascular network development.
• The findings reveal a novel mechanism by which Sema3fb regulates angiogenesis through crosstalk with VEGF signaling.