VEGFD regulates blood vascular development by modulating SOX18 activity.

Area of Science:

• Developmental Biology
• Molecular Biology
• Vascular Biology

Background:

• Vascular Endothelial Growth Factor-D (VEGFD) promotes lymphangiogenesis in tumors and is a therapeutic target for metastasis.
• The endogenous role of VEGFD in normal vascular development has not been fully characterized.
• SoxF transcription factors are involved in vascular development.

Purpose of the Study:

• To investigate the endogenous role of VEGFD in vascular development.
• To identify genetic interactions between the VEGF/VEGF-receptor pathway and SoxF transcription factors.
• To elucidate the molecular mechanisms linking VEGFD and SOXF in vascular endothelial cells.

Main Methods:

• Utilized zebrafish as a model organism to study genetic interactions.
• Performed double knockdown experiments in zebrafish embryos (Sox18/Vegfd and Sox7/Vegfd).
• Generated and analyzed Sox18/Vegfd double knockout mice.
• Investigated the role of VEGFD-MAPK signaling in SOX18-mediated transcription.

Main Results:

• Identified a specific interaction between Vegfd and Sox18.
• Double knockdown of Sox18/Vegfd and Sox7/Vegfd in zebrafish embryos resulted in arteriovenous differentiation defects.
• Sox18/Vegfd double knockout mice exhibited significant vascular development abnormalities, unlike single knockouts.
• VEGFD signaling enhances SOX18 nuclear concentration and transcriptional activity in vascular endothelial cells.

Conclusions:

• VEGFD and Sox18 genetically interact and are essential for normal vascular development, particularly arteriovenous differentiation.
• VEGFD signaling modulates SOX18 transcriptional activity through the MAPK pathway.
• Dysregulation of SOXF-mediated transcriptional networks may underlie VEGFD-associated pathologies.