FRZB-induced anti-angiogenic effect via Caveolin-1-mediated TGFβ signalling

Area of Science:

• Ophthalmology
• Molecular Biology
• Vascular Biology

Background:

• Pathological neovascularization and vascular leakage drive sight-threatening eye diseases.
• Current treatments targeting vascular endothelial growth factor (VEGF) have limitations, necessitating alternative therapies.
• Reduced Frizzled-related Protein (FRZB) levels are observed in proliferative diabetic retinopathy (PDR).

Purpose of the Study:

• To investigate the role of FRZB in ocular angiogenesis.
• To evaluate the therapeutic potential of FRZB and its derivatives in preclinical models of ocular neovascularization.

Main Methods:

• Proteomic analysis of vitreous samples from PDR patients.
• Preclinical models of ocular angiogenesis.
• Administration of Fc-recombinant FRZB and its netrin-related motif (Fc-NTR).
• Assessment of additive effects with Aflibercept.
• Mechanistic studies involving Caveolin-1 (CAV1) and TGFβ signaling pathway.

Main Results:

• Loss of Frzb exacerbates ocular angiogenesis in preclinical models.
• Therapeutic delivery of Fc-recombinant FRZB or Fc-NTR suppressed and reversed ocular angiogenesis.
• Fc-NTR demonstrated additive effects with Aflibercept.
• FRZB was found to bind CAV1, inhibit its phosphorylation, retain the TGFβ receptor ALK5, and enhance Smad2/3 signaling.

Conclusions:

• FRZB acts as a potent endogenous suppressor of ocular angiogenesis.
• FRZB and its derivatives represent a promising therapeutic strategy for neovascular eye diseases.
• Targeting the FRZB-CAV1-TGFβ axis offers a novel therapeutic avenue.