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Kathleen Josephine Jee, Savalan Babapoor, Junaid Hassan, Yassine Daoud, Sharon D Solomon, Gregg L Semenza, Silvia Montaner, Akrit Sodhi; Angiopoietin-like 4 is a Potent Angiogenic Factor in Patients with Proliferative Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5820.
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Proliferative diabetic retinopathy (PDR) is an ischemic retinopathy characterized by retinal neovascularization (NV). In a recent multicenter randomized controlled clinical trial, monthly injection with a monoclonal antibody directed against the potent angiogenic cytokine, vascular endothelial growth factor (VEGF), resulted in a 2/3 reduction - or delay - in the progression to PDR compared to control (sham) treated patients. Although encouraging, this suggests that other factor(s) may drive the development of NV in approximately 1/3 of these patients. Several cytokines have been suggested to promote retinal NV in ischemic retinal disease. We have recently identified angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor upregulated in animal models of ischemic retinal disease. Here we examine the levels of ANGPTL4 in the aqueous fluid (AF) of patients with diabetic retinopathy.
The AF from non-diabetic control (n=60) and diabetic (n=42) patients was collected from consenting patients undergoing cataract or vitrectomy surgery. Levels of VEGF and ANGPTL4 were assessed using an enzyme-linked immunosorbent assay (ELISA). Angiogenic activity was evaluated using an in vitro tubule formation assay.
ELISA analysis of the AF from diabetic patients revealed 38.5% of PDR patients had VEGF levels below the average level detected in control patients. Surprisingly, 100% of AF from low-VEGF PDR patients remained angiogenic (p<0.001). Using in vitro and in vivo approaches, we identified ANGPTL4 as a potent angiogenic cytokine with increased expression in ischemic retinopathies. Levels of ANGPTL4 were increased by 6.7-fold in PDR compared to control patients (p<0.001). Use of an ANGPTL4 blocking antibody inhibited the angiogenic potential of AF of PDR patients with low-VEGF/high-ANGPTL4 levels.
Collectively, our results suggest that inhibition of ANGPTL4 may be an effective approach for the treatment of PDR.
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