Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries

Area of Science:

• Developmental Biology
• Vascular Biology
• Genetics

Background:

• Vessel development involves coordinated arterial, venous, and lymphatic formation.
• Signaling pathways like FLT4 and DLL4 regulate angiogenesis.
• FLT4 is crucial for lymphatic development and has roles in blood vessels.

Purpose of the Study:

• To investigate the mechanisms controlling blood vessel formation in vivo.
• To characterize the function of flt4 in zebrafish vascular development.
• To elucidate the interaction between DLL4 and VEGF-C/FLT4 signaling in arterial development.

Main Methods:

• Forward genetic screen in zebrafish to identify mutants affecting vessel formation.
• Molecular characterization of the 'expando' mutant, identifying a mutation in flt4.
• Analysis of gene knockdown and overexpression effects on arterial angiogenesis and vascular phenotypes.

Main Results:

• Zebrafish flt4 mutants showed defects in lymphatic development but normal arterial angiogenesis.
• Loss of flt4 rescued the arterial hyperbranching phenotype observed in dll4 mutants.
• VEGF-C induced arterial hyperbranching in the absence of DLL4, indicating DLL4 suppresses this response.
• DLL4 knockdown sensitized intersegmental arteries to VEGF-C, while DLL4 overexpression inhibited VEGF-C/FLT4-dependent angiogenesis.

Conclusions:

• DLL4 acts to suppress the responsiveness of developing zebrafish arteries to VEGF-C driven FLT4 signaling.
• This DLL4-mediated suppression contributes to the differential development of arteries and veins in response to VEGF-C.
• The findings reveal a novel mechanism controlling vascular patterning during embryonic development.