September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Role of gremlin, an agonist of vascular endothelial growth factor receptor 2, in retinal angiogenesis
Author Affiliations & Notes
  • Sang Jin Kim
    Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
    Samsung Biomedical Research Institute, Seoul, Korea (the Republic of)
  • JIHYUN YUN
    Samsung Biomedical Research Institute, Seoul, Korea (the Republic of)
  • Ju-A Kim
    Samsung Biomedical Research Institute, Seoul, Korea (the Republic of)
  • Footnotes
    Commercial Relationships   Sang Jin Kim, None; JIHYUN YUN, None; Ju-A Kim , None
  • Footnotes
    Support  This study was supported by Samsung Medical Center grant (#SMX1131941 and #SMR1120521) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HI13C1826).
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3648. doi:
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    • Get Citation

      Sang Jin Kim, JIHYUN YUN, Ju-A Kim; Role of gremlin, an agonist of vascular endothelial growth factor receptor 2, in retinal angiogenesis. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3648.

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

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Abstract

Purpose : Gremlin is a bone morphogenic protein antagonist and also a direct agonist of vascular endothelial growth factor receptor 2 (VEGFR2), a major proangiogenic receptor. Gremlin was reported to be expressed in the retina of non-diabetic and diabetic mice. However, the role of gremlin in retinal angiogenesis has not been reported. We investigated the angiogenic effect of gremlin in human endothelial cells and examined the expression in a mouse model of oxygen-induced retinopathy (OIR).

Methods : Tube formation assays were performed using human umbilical vein endothelial cells (HUVEC) and human retinal microvascular endothelial cells (HRMEC) to determine the angiogenic activity of gremlin compared to VEGF. In brief, HUVEC and HRMEC treated either with VEGF (10 and 100 ng/ml) or gremlin (10 and 100 ng/ml) were seeded and the tubular structures were manually quantified. Also, the effect of adding tanibirumab, a fully human monoclonal antibody against VEGFR2, was examined in HUVEC and HRMEC. The mouse model of OIR was induced by exposing C57BL/6 mice on postnatal day 7 (P7) to 75% hyperoxia for 5 days, followed by 5 days in room air. Retinas from mice on P12 and P17 were isolated and subjected to molecular and histological analyses.

Results : Gremlin and VEGF were equally effective in promoting tube formation in both HUVEC and HRMEC. Tanibirumab significantly reduced the tube formation in both gremlin and VEGF treated endothelial cells. In the OIR mouse model, the gremlin mRNA level in P17 retina was increased 2.9 fold and 12.8 fold compared to normal control retina and P12 retina, respectively. Also, western blot analysis showed that gremlin protein was significantly increased in P17 retina. Immunofluorescence analysis showed gremlin was expressed mainly in the inner retina, including nerve fiber, ganglion cell, and inner nuclear layers in P17 retina.

Conclusions : The results suggest that gremlin may play an important role in retinal angiogenesis. Further investigation is warranted to clarify the in vivo effect of gremlin in retinal angiogenesis.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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