Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization.

Abstract

Neovascular diseases of the retina are a major cause of blindness worldwide. Hypoxia is thought to be a common precursor to neovascularization in many retinal diseases, but the factors involved in the hypoxic neovascular response have not been fully identified. To Retinal neovascularization is a major cause of blindness in the United States (1). Pathologic retinal angiogenesis is a final common pathway leading to vision loss in diseases such as retinopathy of prematurity (ROP), diabetic retinopathy, and age-related macular degeneration (2-4). Despite the prevalence of these diseases, the biochemical events responsible for retinal neovascularization are not fully understood. It is hoped that a better understanding of the fundamental basis of retinal neovascularization will improve treatment and prevention of retinal vascular diseases.In these eye diseases, as in tumor growth and wound healing, hypoxia appears to be a common precursor to neovascularization (5, 6). In the 1940s and 1950s, Michaelson (7) and Ashton et al. (8) postulated that retinal neovascularization was caused by release of a "vasoformative factor" from the retina in response to hypoxia. Since these initial hypotheses, it has become widely accepted that retinal hypoxia results in the release of factors that influence new blood vessel growth (3). The angiogenic factors responsible for retinal neovascularization, however, have not been conclusively identified.Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial cell-specific mitogen that was identified and cloned by several groups of investigators (9-12). The expression of VEGF/VPF is stimulated by hypoxia, and VEGF/VPF has been demonstrated to be required for tumor-associated angiogenesis (13)(14)(15) (17)(18)(19)(20). VEGF/VPF levels also increase in a primate model of iris neovascularization (21). However, the location and time course of VEGF/VPF expression in association with retinal neovascularization has not been delineated nor has it been determined if VEGF/VPF has a direct role in the induction of retinal neovascularization.The goal of the present study was to examine the role of VEGF/VPF in retinal neovascularization by studying the time course and location of VEGF/VPF expression in a mouse model of proliferative retinopathy (22). In this model, mice are exposed to hyperoxia, resulting in obliteration of the posterior retinal vessels. The mice are then returned to room air, which is presumed to cause relative hypoxia of the now nonperfused retina, producing a quantifiable neovascular response in 100% of animals. Using this model, the expression of VEGF/VPF mRNA and protein were studied by RNA (Northern) blot analysis, in situ hybridization, and immunohistochemical confocal microscopy. These data demonstrate the role of VEGF/ VPF in an animal model of retinal neovascularization, which has not previously been done to our knowledge.EXPERIMENTAL PROCEDURES Mouse Model. The study adhered to the "Association for Research in Vision and Ophthalmolog...

Vascular endothelial growth factor in eye disease

“…In situ hybridization and western blot experiments have shown VEGF expression to be decreased during the hyperoxic phase of oxygen-exposed mice compared to normal control animals, with an increase in VEGF mRNA and protein expression in the Müller cells of the inner nuclear layer within six hours of removal to room air (Pierce et al, 1995;Pierce et al, 1996;Ozaki et al, 1999). Notably, HIF-1 expression is increased in the inner nuclear layer prior to any increase in VEGF mRNA expression in OIR mice (Ozaki et al, 1999).…”

Glia: the fulcrum of brain diseases

“…52 Finally, the pathological scenario involves a dramatic change in the cytokine release pattern of the Mü ller cells (Figure 2b, IV). Oedema/pressure-mediated reduction of retinal blood flow and excitotoxic overstimulation of neuronal metabolism contribute to retinal hypoxia which stimulates the release of VEGF from Mü ller cells 53 and retinal pigment epithelial (RPE) cells. 54 Increased VEGF levels make the retinal vasculature leaky, which, in turn, leads to increased efflux of water (i.e., to aggravated oedema) and to the release of a variety of cytokines from vessels into the retinal tissue.…”

Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-γ and migration of endothelial cells expressing Flt 1

“…In addition to its growth promoting e ect, VEGF induces increased permeability of vascular endothelial cells and stimulates angiogenesis . The expression of VEGF is upregulated by hypoxia and VEGF plays a role in many pathological processes such as tumour vascularization and proliferative retinopathy (Pierce et al, 1995;Plate et al, 1994;Shweiki et al, 1992). VEGF exerts its activity by binding to and activating cell surface receptor tyrosine kinases.…”