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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)
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).
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.
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).
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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