Differential expression of pro- and antiangiogenic factors in mouse strain-dependent hypoxia-induced retinal neovascularization

Abstract

Clinical observations suggest that genetic factors may influence heterogeneity of angiogenic responses in cardiovascular disease, proliferative diabetic retinopathy, and neoplasia. Experiments among mouse strains using a corneal micropocket assay indicate that extent of angiogenesis may be genetically determined. Here, we established the strain-dependence of hypoxia-induced retinal angiogenesis in multiple mouse strains which paralleled the rank order found for bFGF-induced corneal angiogenesis. Using quantitative real-time RT-PCR, strain-related gene expression differences in retina/choroid between C57BL/6J and 129S3/SvIM, inbred strains with relatively low and high levels of angiogenesis, respectively, after 0, 6, 12, 24, 48, and 96 h hypoxia were determined for vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), angiogenic ligands potently induced by hypoxia, and for pigment epithelium-derived factor (PEDF) and thrombospondin-1 (TSP-1), endogenous broad-spectrum antiangiogenic factors. Indirect ELISA was used to correlate VEGF and PEDF protein levels with mRNA expression. At the onset of hypoxia, both PEDF and TSP-1 levels were increased over 15-fold and VEGF was increased over 10-fold compared to Ang-2 in both strains. At the onset of neovascularization (48 h), both VEGF and Ang-2 mRNA levels were increased in the more angiogenic 129S3/ SvIM strain (Po0.02), which was not observed among developmental control animals. PEDF expression was higher in the less angiogenic C57BL/6J strain at 6, 12, 24, and 96 h hypoxia (Po0.03), while TSP-1 expression was higher in C57BL/6J throughout the entire time course of hypoxia (4 days) compared to 129S3/SvIM (Po0.02). Among developmental control animals, PEDF and TSP-1 expression was also increased at P14 and P16 in C57BL/6J strain compared to 129S3/SvIM (Po0.02). Strain-dependent expression of both pro-and antiangiogenic growth factors may determine heterogeneity in the angiogenic response and potentially, susceptibility to angiogenesis-dependent diseases.

Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro

“…12,41,42 How then do we explain the absence of Cd151 gene deletion effects in the oxygen-induced retinopathy (OIR) model? Retinal vascularization may be uniquely dependent on a preexisting astrocytic template.…”

Vascular endothelial growth factor in eye disease

“…In retinal endothelial cells, VEGF downregulated PEDF (Zhang et al, 2006b). There is also evidence that variability in oxygen-induced angiogenic responses in different strains of mice and rats is related to differences in VEGF and PEDF expression, VEGF lower and PEDF higher in the less angiogenic strains (Chan et al, 2005;Gao et al, 2001). In rats, part of the mechanism appears to be from a mediator upstream from the VEGF gene and promoter (Lu et al, 2007).…”

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

“…Many of these animal studies stem from genetically distinct mouse strains, such as the rd mouse, which possesses a mutation of rod-specific phosphodiesterase (Bowes et al, 1990;Jimenez et al, 1996). Other studies have focused attention on strain differences and metabolic consequences of light damage on retina during neonatal hyperoxia (Chan et al, 2005;Wu et al, 2006). However, much less is known about the environmental and metabolic contribution of tissue hypoxia to this process.…”