Loss of the Antiangiogenic Pigment Epithelium-Derived Factor in Patients With Angiogenic Eye Disease

Abstract

Retinal neovascularization characterizes proliferative diabetic retinopathy (PDR). Pigment epithelium-derived factor (PEDF) has been shown to be a major antiangiogenic growth factor in the mammalian eye. PEDF expression is suppressed by hypoxia, and changes in PEDF have been correlated to the development of retinal neovascularization in animal models of hypoxic eye disease. However, whether this concept of a reduced angiogenesis inhibitor holds true in humans is as yet unclear. In this study, we analyzed the in vivo regulation of PEDF in patients with and without hypoxic eye disease. We used immunoblots to measure PEDF in ocular fluids obtained from 64 nondiabetic and diabetic patients. In addition, immunohistochemistry of PEDF was carried out in specimens of normal human retinas and retinas with various degrees of diabetic retinopathy. The PEDF concentrations in patients with PDR (P < 0.001) or extensive nondiabetic retinal neovascularization caused by retinal-vein occlusion (P < 0.001) were lower than in control patients. Levels of PEDF were replenished in PDR patients with previous retinal scatter photocoagulation compared with PDR patients without previous photocoagulation (P ‫؍‬ 0.01). Immunohistochemistry revealed an interstitial staining pattern as expected for a secreted protein, with an intense staining in retinas of patients without proliferative eye disease. However, in patients with PDR, little or no staining was detectable. Our data strongly support the concept that retinal angiogenesis is induced by loss of the major angiogenesis inhibitor in the eye, PEDF, in combination with an increased expression of angiogenic growth factors such as vascular endothelial growth factor. Our findings suggest that substitution of angiogenesis inhibitors may be an effective approach in the treatment of PDR. Diabetes 50: [2641][2642][2643][2644][2645] 2001 T he control of retinal angiogenesis is of critical importance for the preservation of vision. Retinal neovascularization characterizes proliferative diabetic retinopathy (PDR), which is still one of the most common causes of blindness worldwide. Retinal ischemia induces intraocular neovascularization, presumably by stimulating the expression of angiogenic growth factors and by inhibiting the release of antiangiogenic cytokines (1,2). Vitreal levels of angiogenic growth factors have been shown to be directly associated with the degree of retinal angiogenesis (3,4). The ability to monitor and grade retinal angiogenesis within the eye as well as the ability to aspirate vitreous, which is known to contain retina-derived growth factors in direct association to the stage of retinal angiogenesis, makes the eye an ideal setting in which to investigate the delicate balance of new vessel growth and the influence of specific growth factors in vivo in humans.Pigment epithelium-derived factor (PEDF) protects cerebellar granule cells against neurotoxic agents (5) and is also called early population doubling level cDNA-1 (EPC-1), reflecting its upregulation during cell cycle ...

Pigment epithelium-derived factor in the monkey retinal pigment epithelium and interphotoreceptor matrix: apical secretion and distribution

“…The levels of PEDF in monkey vitreous are within the range of those reported previously in humans, e.g. 23·7^0·7 nM (Spranger et al, 2001), 1·7^0·22 mg ml 21 (Ogata et al, 2002), with the exception of one, about 16 mg ml 21 (Holekamp et al, 2002). It is expected that the determinations of PEDF concentrations in the monkey IPM and aqueous are also within the range of those in their human counterparts.…”

“…Changes in PEDF levels in the eye with angiogenic retina or retinal degenerations may contribute to the development or progression of these disorders. Evidence for an association between decreased PEDF and induced or diseased-related angiogenesis (Spranger et al, 2001;Gao et al, 2002;Ogata et al, 2002;Holekamp et al, 2002) makes the present information on physiological PEDF levels more valuable for diagnostic and therapeutic studies.…”

Proteomic analysis of human vitreous fluid by fluorescence-based difference gel electrophoresis (DIGE): a new strategy for identifying potential candidates in the pathogenesis of proliferative diabetic retinopathy

“…Among the proteins with decreased abundance, we identified PEDF, a protein with anti-angiogenic properties, which has previously been reported to be decreased in the vitreous fluid of PDR patients [15,16]. The identification of this protein as decreased in abundance, as would be expected, provides an internal control for this comparative proteomic analysis.…”

“…Apart from its neurotrophic and neuroprotective properties, there is growing evidence to suggest that PEDF is among the most important natural inhibitors of angiogenesis, and that it is the main factor accounting for the anti-angiogenic activity of the vitreous fluid, where it is found in abundant quantities [32,33]. The relevance of PEDF to human neovascular disease is supported by studies showing that decreased levels of PEDF in the vitreous are associated with PDR [15,16]. We have confirmed a PEDF deficit in the vitreous fluid of diabetic patients with PDR by both proteomic analysis and western blotting.…”

Overexpression of Pigment Epithelium-Derived Factor Decreases Angiogenesis and Inhibits the Growth of Human Malignant Melanoma Cells in Vivo

“…5,6 Furthermore, loss of PEDF was associated with angiogenic activity in proliferative diabetic retinopathy. 7 However, a functional role for PEDF in tumor growth and angiogenesis remains to be elucidated.…”