September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Pleiotrophin as a Novel Target for Anti-Angiogenic Therapy of Diabetic Retinopathy
Author Affiliations & Notes
  • Weiwen Wang
    Department of Ophthalmology, University of Miami, Miami, Florida, United States
  • Michelle Elizabeth LeBlanc
    Department of Ophthalmology, University of Miami, Miami, Florida, United States
  • XIUPING CHEN
    Department of Ophthalmology, University of Miami, Miami, Florida, United States
    Zhongshan Hospital, Shanghai, China
  • Yanli Ji
    Department of Ophthalmology, University of Miami, Miami, Florida, United States
    Second People's Hospital of Zhengzhou, Zhengzhou, China
  • Megan Brewer
    Department of Ophthalmology, University of Miami, Miami, Florida, United States
  • Vivianne Gonzalez
    Department of Ophthalmology, University of Miami, Miami, Florida, United States
  • Wei Li
    Department of Ophthalmology, University of Miami, Miami, Florida, United States
  • Footnotes
    Commercial Relationships   Weiwen Wang, None; Michelle LeBlanc, None; XIUPING CHEN, None; Yanli Ji, None; Megan Brewer, None; Vivianne Gonzalez, None; Wei Li, None
  • Footnotes
    Support  NIH R01GM094449 (W.L.), R21HD075372 (W.L.), BrightFocus Foundation M2012026 (W.L.), Special Scholar Award from Research to Prevent Blindness (RPB) (W.L.), K99EY020865/R00EY020865 (N.B.C.), American Heart Association (AHA) Predoctoral Fellowship 14PRE18310014 (M.E.L), P30-EY014801 and an institutional grant from RPB.
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5048. doi:
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      Weiwen Wang, Michelle Elizabeth LeBlanc, XIUPING CHEN, Yanli Ji, Megan Brewer, Vivianne Gonzalez, Wei Li; Pleiotrophin as a Novel Target for Anti-Angiogenic Therapy of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5048.

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

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Abstract

Purpose : Anti-VEGF (vascular endothelial growth factor) therapy has been approved to treat diabetic macular edema (DME) but with only ~21-50% efficacy. A recent report showed that pleiotrophin (PTN), a known angiogenic factor, is upregulated in the vitreous fluid of proliferative diabetic retinopathy (PDR) patients, implying that PTN may involve in the pathogenesis. Here we hypothesize that PTN is a novel potential target for anti-angiogenic therapy of diabetic retinopathy (DR).

Methods : In vitro angiogenesis assays were performed in human retinal microvascular endothelial cells (HRMVECs) in the presence of PTN, VEGF or PBS. Activated ERK1/2 and AKT kinases were detected by Western blot. Corneal pocket assay (PBS, n=8; VEGF, n=5; PTN, n=8) was performed to confirm the angiogenic activity of PTN in vivo. Healthy C57BL/6 mice (6-8 weeks old) were intravitreally injected with PTN (0.5 mg, n=6), VEGF (0.2 mg, n=4) or control (n=4) and the retinal vascular leakage was quantified by Evans blue assay. C57BL/6 mice (male, 6 weeks old) were intraperitoneally treated with streptozotocin to induce diabetes and aged for 4 months to develop DR with retinal leakage. DR mice were intravitreally treated with PTN-neutralizing antibody (1.28 mg/eye, n=6), Eylea (2 mg/eye, n=5) or control IgG (n=5). Oxygen-induced retinopathy (OIR) was induced in neonatal mice as a model of PDR and was treated in a similar manner.

Results : PTN stimulated the proliferation (p<0.01), migration (p<0.05) and spheroid sprouting (p<0.001) of HRMVECs in vitro and promoted corneal angiogenesis (p<0.01) in vivo. PTN activated both ERK1/2 and AKT in HRMVECs. Compared to IgG control, intravitreal injection of PTN and VEGF in healthy mice increased retinal vascular leakage by 2.50 ± 0.38 and 5.77 ± 0.87 folds, respectively. Importantly, intravitreal injection of PTN-neutralizing antibody or Eylea alleviated retinal vascular leakage in diabetic mice by 65 ± 11% and 74 ± 8%, respectively. Furthermore, anti-PTN antibody prevented pathological angiogenesis in OIR mice, including percentage of neovascularization area (p<0.05), neovascular tufts (p<0.05) and vessel branching points (p<0.01).

Conclusions : Our results suggest that PTN promotes retinal angiogenesis both in vitro and in vivo. Blocking PTN significantly reduces the symptoms of DR in mice model and therefore may be a promising alternative therapy of DR.

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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