Redundant Mechanisms for Vascular Growth Factors in Retinopathy of Prematurity in vitro

Abstract

Background: Current treatments for retinopathy of prematurity (ROP) targeting single vascular growth factors are ineffective in preventing neoangiogenesis. Methods: We investigated the redundant/compensatory mechanisms between vascular growth factors in ROP. Cultured retinal vascular endothelial cells under CoCl₂-induced hypoxia were transfected with recombinant adeno-associated virus type 2-vascular endothelial growth factor (VEGF) or pGIPZ-VEGF RNA interference to up- and downregulate VEGF expression, respectively. At 48 h after transfection, basic fibroblast growth factor (bFGF) and angiopoietin 1 (ANG1) gene expression as well as mitotic cycle changes were analyzed in the cells and correlated with the change in VEGF expression. Results: Compared with the normal control group 1, at 30 min, 12 h and 24 h, the expressions of VEGF, bFGF and ANG1 in the hypoxia control group 2 were significantly higher. In the highly expressing VEGF group (group 3), the expressions of bFGF and ANG1 were downregulated, while in the low-expressing VEGF group 4, the expressions of bFGF and ANG1 were significantly upregulated. In the bevacizumab treatment group 5, the expressions of VEGF, bFGF and ANG1 were similar to those in group 2, and the difference was not significant. Conclusions: A compensatory mechanism (redundancy) exists between vascular growth factors in ROP. Such a phenomenon could partially explain why the inhibition of a single growth factor cannot effectively prevent the recurrence of neovascularization in ROP. A more effective strategy for treating ROP may be to inhibit VEGF and its redundant pathways.

A Murine Model for Retinopathy of Prematurity Identifies Endothelial Cell Proliferation as a Potential Mechanism for Plus Disease

“…[24][25][26][27][28] This hypothesis is directly supported by our observation that intravitreal injection of the VEGF-A antagonist bevacizumab strongly reduced the development of vascular tortuosity in the OIR model, consistent with a recent report by Rabinowitz et al, 29 and prevented dilation of veins as well as proliferation of endothelial cells. This model also suggests that plus disease should correlate with the level of VEGF produced during the hypoxic phase of ROP.…”

3,4 dihydroxyphenyl ethanol reduces secretion of angiogenin in human retinal pigment epithelial cells

“…Forooghian et al show significant increases of intraocular inflammatory cytokine secretions (such as Il-8 and TGF-β 2 ) in patients with proliferative diabetic retinopathy (PDR) following intravitreal injection of bevacizumab. Another report by Xiang et al 14 demonstrated an increased expression of angiopoietin1 and bFGF1 in retinal vascular endothelial cells in low-expressing VEGF groups in patients with retinopathy of prematurity. These studies support the notion that compensatory mechanisms may be at play following intraocular delivery of bevacizumab.…”

Intravitreal Injection of TIMP3 or the EGFR Inhibitor Erlotinib Offers Protection from Oxygen-Induced Retinopathy in Mice

“…6,8,11,[35][36][37][38] Conditional knockout mice lacking ADAM17 in endothelial cells show decreased revascularization of the central avascular area 5 ; these results are therefore consistent with a model in which the lack of TIMP3 increases the activity of ADAM17, which in turn could increase revascularization, whereas injection of TIMP3 could prevent revascularization by blocking ADAM17. VEGF-A is highly upregulated in mouse OIR, [39][40][41] and previous studies have shown that VEGF-A/VEGFR2 signaling activates ADAM17 to promote crosstalk with the EGFR and stimulate migration of endothelial cells. 29,30 Since the injection of TIMP3 might also affect the binding of VEGF-A to the VEGFR2, 21 injection of TIMP3 could interfere with pathological neovascularization by inhibiting two crucial components of this pathway, binding of VEGF-A to the VEGFR2 and the activation of ADAM17.…”