June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Secreted frizzled-related protein (SFRP) serves as a potent antiangiogenic factor
Author Affiliations & Notes
  • Xiaomeng Wang
    Singapore Eye Research Institute, Singapore, Singapore
    Duke-NUS Medical School, Singapore, Singapore
  • Beiying Qiu
    Singapore Eye Research Institute, Singapore, Singapore
    Duke-NUS Medical School, Singapore, Singapore
  • Alison Tan
    Singapore Eye Research Institute, Singapore, Singapore
    Duke-NUS Medical School, Singapore, Singapore
  • Amutha Veluchamy
    Singapore Eye Research Institute, Singapore, Singapore
    Duke-NUS Medical School, Singapore, Singapore
  • Sze Yuan Ho
    Singapore Eye Research Institute, Singapore, Singapore
    Duke-NUS Medical School, Singapore, Singapore
  • Lei Zhou
    Singapore Eye Research Institute, Singapore, Singapore
    Duke-NUS Medical School, Singapore, Singapore
  • Ning Cheung
    Singapore Eye Research Institute, Singapore, Singapore
    Singapore National Eye Centre, Singapore, Singapore, Singapore
  • Gemmy Cheung Chui Ming
    Singapore National Eye Centre, Singapore, Singapore, Singapore
    Duke-NUS Medical School, Singapore, Singapore
  • Tien Wong
    Singapore National Eye Centre, Singapore, Singapore, Singapore
    Duke-NUS Medical School, Singapore, Singapore
  • Wanjin Hong
    Institute of Molecular and Cell Biology, Singapore, Singapore
  • Footnotes
    Commercial Relationships   Xiaomeng Wang None; Beiying Qiu None; Alison Tan None; Amutha Veluchamy None; Sze Yuan Ho None; Lei Zhou None; Ning Cheung None; Gemmy Cheung Chui Ming Roche, Novartis, Roche, Code C (Consultant/Contractor), Novartis, Bayer, Boehringer-Ingelheim, Topcon, Code F (Financial Support); Tien Wong Allergan, Bayer, Boehringer-Ingelheim, Eden Ophthalmic, Genentech, Iveric Bio, Merck, Novartis, Oxurion (ThromboGenics), Roche, Samsung, Shanghai Henlius, Zhaoke Pharmaceutical, Code C (Consultant/Contractor), Plano, EyRiS, Code O (Owner); Wanjin Hong None
  • Footnotes
    Support  BMRC-SIPRAD, NMRC/OFLCG/004/2018
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 781 – F0340. doi:
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    • Get Citation

      Xiaomeng Wang, Beiying Qiu, Alison Tan, Amutha Veluchamy, Sze Yuan Ho, Lei Zhou, Ning Cheung, Gemmy Cheung Chui Ming, Tien Wong, Wanjin Hong; Secreted frizzled-related protein (SFRP) serves as a potent antiangiogenic factor. Invest. Ophthalmol. Vis. Sci. 2022;63(7):781 – F0340.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Abnormal angiogenesis is a characteristic feature of many blinding eye diseases, including proliferative diabetic retinopathy (PDR) and neovascular age-related macular degeneration (nAMD). Inhibiting excessive blood vessel growth and leakage is effective in preserving vision. Current anti-angiogenic drugs are dominated by vascular endothelial growth factor (VEGF) inhibitors. However, a substantial number of patients do not respond well to anti-VEGF drugs. Targeting VEGF independent pathways may offer an alternative strategy to treat ocular angiogenic diseases.

Methods : Proteomic analysis was performed in vitreous samples collected from PDR and control patients. Human secreted frizzled-related protein (SFRP) and its C-terminal domain were fused to Fc to generate chimera protein SFRP-Fc and SFPRC-Fc. Their impacts on endothelial cell proliferation and tube formation were studied using in vitro cell-based assays. Ex vivo angiogenesis assays including choroid, aortic ring, and metatarsal assays were used to study the anti-angiogenic effect of SFRP-Fc and SFRPC-Fc in a multi-cellular environment. The efficacies of SFRP-Fc and SFRPC-Fc were further evaluated in a mouse model laser-induced choroidal neovascularization (CNV) and a rabbit model of persistent retinal neovascularization (PRNV). Phosphoproteomics, quantitative RT-PCR, and Western bot analysis were used to investigate the mechanism of action of SFRP.

Results : Our study showed that SFRP is expressed at a significantly lower level in the vitreous of PDR patients as compared to that in control patients. SFRP-Fc and SFRPC-Fc strongly inhibit human retinal microvascular endothelial cell (HREC) proliferation, viability, and tube formation as well as vessel outgrowth from the choroid, aortic ring, and metatarsal bones. SFRPC-Fc is able to prevent and reverse laser-induced CNV in mice and demonstrates an additive effect with Aflibercept. In the rabbit model of PRNV, a single intravitreal injection of 2mg SFPRC-Fc could lead to persistent suppression of retinal angiogenesis and leakage for at least six weeks. Mechanistically, SFRP inhibits angiogenesis in a VEGF-independent fashion via Caveolin-1.

Conclusions : This study leads to the discovery of a novel inhibitor of angiogenesis SFRP and confirmed that its functional domain is located at the C-terminal domain of the protein. We further showed that SFRP exerts its anti-angiogenic effect through Caveolin-1.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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