title: Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy.
abstract: Diabetic eye disease is the most common cause of severe vision loss in the working-age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela. In PDR, retinal ischemia leads to the up-regulation of angiogenic factors that promote neovascularization. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization in some, but not all, diabetic patients, implicating additional factor(s) in PDR pathogenesis. Here we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identify angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor whose expression is up-regulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization. Inhibition of ANGPTL4 expression reduced the angiogenic potential of hypoxic Müller cells; this effect was additive with inhibition of VEGF expression. An ANGPTL4 neutralizing antibody inhibited the angiogenic effect of aqueous fluid from PDR patients, including samples from patients with low VEGF levels or receiving anti-VEGF therapy. Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of PDR and provide the foundation for studies evaluating aqueous ANGPTL4 as a biomarker to help guide individualized therapy for diabetic eye disease.
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Savalan
authors.initials: S
authors.lastname: Babapoor-Farrokhran
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Kathleen
authors.initials: K
authors.lastname: Jee
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Brooks
authors.initials: B
authors.lastname: Puchner
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Syed Junaid
authors.initials: SJ
authors.lastname: Hassan
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Xiaoban
authors.initials: X
authors.lastname: Xin
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Murilo
authors.initials: M
authors.lastname: Rodrigues
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Fabiana
authors.initials: F
authors.lastname: Kashiwabuchi
authors.affiliation: Department of Oncology and Diagnostic Sciences, School of Dentistry, and Department of Pathology, School of Medicine, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201;
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287; Department of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Hu
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Monika
authors.initials: M
authors.lastname: Deshpande
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Yassine
authors.initials: Y
authors.lastname: Daoud
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Sharon
authors.initials: S
authors.lastname: Solomon
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Adam
authors.initials: A
authors.lastname: Wenick
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Lutty
authors.affiliation: Vascular Program, Institute for Cell Engineering, and Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205;
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: Department of Oncology and Diagnostic Sciences, School of Dentistry, and Department of Pathology, School of Medicine, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201;
authors.forename: Silvia
authors.initials: S
authors.lastname: Montaner
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287; asodhi1@jhmi.edu.
authors.forename: Akrit
authors.initials: A
authors.lastname: Sodhi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042682:Angiopoietins / Q000378:metabolism / Q000502:physiology*; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism; D005123:Eye / Q000098:blood supply / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D042682:Angiopoietins; D042461:Vascular Endothelial Growth Factor A; C118117:angiopoietin 4
keywords: angiopoietin-like 4; diabetes; hypoxia inducible factor-1; neovascularization; vascular endothelial growth factor