Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis

Area of Science:

• Biochemistry
• Molecular Biology
• Vascular Biology

Background:

• Current antiangiogenic therapies targeting vascular endothelial growth factor (VEGF) face limitations due to resistance and insufficient efficacy.
• Genetic studies identified phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) as a promoter of vessel formation.

Purpose of the Study:

• To investigate the antiangiogenic therapeutic potential of blocking PFKFB3.

Main Methods:

• Utilized the small molecule 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) to inhibit PFKFB3.
• Assessed vessel sprouting in endothelial cell spheroids, zebrafish embryos, and the postnatal mouse retina.
• Evaluated the effect of 3PO on vascular hyperbranching and its synergy with VEGF blockade.
• Examined pathological neovascularization in ocular and inflammatory models.

Main Results:

• 3PO blockade of PFKFB3 reduced vessel sprouting by inhibiting endothelial cell proliferation and migration.
• 3PO suppressed vascular hyperbranching induced by Notch or VEGFR1 inhibition.
• 3PO amplified the antiangiogenic effect of VEGF blockade.
• Partial and transient reduction in glycolysis by 3PO in vivo was sufficient to decrease pathological neovascularization.

Conclusions:

• PFKFB3 blockade represents a promising alternative antiangiogenic strategy.
• 3PO demonstrates therapeutic potential for treating pathological neovascularization in various models.
• Targeting PFKFB3 offers new avenues for antiangiogenic therapies.