FGF-dependent metabolic control of vascular development

Area of Science:

• Vascular biology
• Cellular metabolism
• Molecular signaling

Background:

• Blood and lymphatic vessels are vital for tissue oxygenation and fluid balance.
• Endothelial cell sprouting, migration, and proliferation are key to vascular network assembly.
• Cellular metabolism significantly influences vascular development, with VEGF signaling well-studied, but FGF roles are less understood.

Purpose of the Study:

• To investigate the role of fibroblast growth factors (FGFs) in vascular development and metabolism.
• To elucidate the molecular mechanisms by which FGF signaling impacts endothelial cell function.

Main Methods:

• Investigated FGF receptor (FGFR) signaling pathways in endothelial cells.
• Analyzed the regulation of c-MYC (MYC) and hexokinase 2 (HK2) expression.
• Utilized knockout mouse models (pan-endothelial and lymphatic-specific Hk2 knockouts, Fgfr1/Fgfr3 double mutants).
• Assessed the impact of HK2 overexpression on FGF signaling-deficient cells.

Main Results:

• FGFR signaling critically regulates vascular development.
• FGF signaling controls MYC expression, which in turn regulates HK2.
• Reduced HK2 levels impair endothelial cell glycolysis, proliferation, and migration.
• Hk2 knockouts phenocopy vascular defects seen in Fgfr1/Fgfr3 mutants.
• HK2 overexpression partially rescues FGF signaling suppression-induced defects.

Conclusions:

• FGF signaling is a pivotal regulator of endothelial glycolysis.
• This FGF-dependent metabolic regulation is essential for developmental and adult vascular growth.