Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function.

Department of Cell Biology, Harvard Medical School, 188 Longwood Ave., Boston, MA 02115, USA.
American Journal Of Pathology (Impact Factor: 4.6). 12/2005; 167(5):1451-9. DOI: 10.1016/S0002-9440(10)61231-X
Source: PubMed

ABSTRACT The choroid in the eye provides vascular support for the retinal pigment epithelium (RPE) and the photoreceptors. Vascular endothelial growth factor (VEGF) derived from the RPE has been implicated in the physiological regulation of the choroidal vasculature, and overexpression of VEGF in this epithelium has been considered an important factor in the pathogenesis of choroidal neovascularization in age-related macular degeneration. Here, we demonstrate that RPE-derived VEGF is essential for choriocapillaris development. Conditional inactivation of VEGF expression in the RPE (in VEGFrpe-/- mice) results in the absence of choriocapillaris, occurrence of microphthalmia, and the loss of visual function. Severe abnormalities of RPE cells are already observed when VEGF expression in the RPE is only reduced (in VEGFrpe+/- mice), despite the formation of choroidal vessels at these VEGF levels. Finally, using Hif1arpe-/- mice we demonstrate that these roles of VEGF are not dependent on hypoxia-inducible factor-1alpha-mediated transcriptional regulation of VEGF expression in the RPE. Thus, hypoxia-inducible factor-1alpha-independent expression of VEGF is essential for choroid development.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The central role of vascular endothelial growth factor (VEGF) signaling in regulating normal vascular development and pathological angiogenesis has been documented in multiple studies. Ocular anti-VEGF therapy is highly effective for treating a subset of patients with blinding eye disorders such as diabetic retinopathy and neovascular age-related macular degeneration (AMD). However, chronic VEGF suppression can lead to adverse effects associated with poor visual outcomes due to the loss of prosurvival and neurotrophic capacities of VEGF. In this review, we discuss emerging evidence for immune-related mechanisms that regulate ocular angiogenesis in a VEGF-independent manner. These novel molecular and cellular pathways may provide potential therapeutic avenues for a multitarget strategy, preserving the neuroprotective functions of VEGF in those patients whose disease is unresponsive to VEGF neutralization. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Trends in Molecular Medicine 11/2014; 21(1). DOI:10.1016/j.molmed.2014.10.005 · 10.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate retinal morphology and function of patients with advanced neovascular age-related macular degeneration (AMD) before, during, and after treatment with ranibizumab. Twenty-one eyes diagnosed with advanced AMD were studied with optical coherence tomography (OCT) and multifocal electroretinography (mfERG). Three intravitreal injections of ranibizumab were administered at 1-month intervals. Evaluations were performed before the first injection (D0) and at 30 (D30), 60 (D60), and 90 days (D90) after the first injection and compared to an age-matched control group (n=21 eyes). The thickness of macular retinal layers increased before treatment due to the presence of intraretinal fluid. A thick retinal pigment epithelium-choriocapillaris complex (RPE-CC) suggested the presence of choroidal neovascular membrane. Intraretinal edema decreased after treatment (P<0.01), but persisting RPE-CC thickness resulted in a subretinal scar. Three different annular retinal areas were studied with mfERG (from center to periphery: rings R1, R2, and R3). The amplitude of the first negative component (N1) decreased in R1, R2, and R3 at D30, D60, and D90 when compared with that in controls (P<0.05); the N1 implicit time was delayed in R3 at D30 (P<0.05). The amplitude of the first positive component (P1) was reduced in R1 and R2 at D30, D60, and D90 when compared with that in controls (P<0.01); the P1 implicit time was delayed in R1 at D0 and D60 (P<0.05), in R2 at D0, D30, and D90 (P<0.01), and in R3 at D30 and D60 (P<0.05). Ranibizumab reduces intraretinal edema, even in advanced cases. Central macular activity appeared to increase after the initiation of treatment, improving over time.
    Arquivos Brasileiros de Oftalmologia 02/2015; 78(2):105-9. DOI:10.5935/0004-2749.20150027 · 0.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Vision loss due to vascular disease of the retina is a leading cause of blindness in the world. Retinal angiomatous proliferation (RAP) is a subgroup of neovascular age-related macular degeneration (AMD), whereby abnormal blood vessels develop in the retina leading to debilitating vision loss and eventual blindness. The novel mouse strain, neoretinal vascularization 2 (NRV2), shows spontaneous fundus changes associated with abnormal neovascularization. The purpose of this study is to characterize the induction of pathologic angiogenesis in this mouse model.
    PLoS ONE 09/2014; 9(9):e106507. DOI:10.1371/journal.pone.0106507 · 3.53 Impact Factor