Müller cell‐derived VEGF is a significant contributor to retinal neovascularization

Abstract

Vascular endothelial growth factor (VEGF-A) is a major pathogenic factor and a therapeutic target for age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. Despite intensive effort in the field, the cellular mechanisms of VEGF action remain virtually uninvestigated. This situation makes it difficult to design cellular target-based therapeutics for these diseases. In light of the recent finding that VEGF is a potential neurotrophic factor, revealing the cellular mechanisms of VEGF action becomes necessary to preserve its beneficial effect and inhibit its pathological function in long-term anti-VEGF therapeutics for ocular vascular diseases. We therefore generated conditional VEGF knockout mice with an inducible Cre/lox system and determined the significance of Müller cell-derived VEGF in retinal development and maintenance and ischaemia-induced neovascularizartion and vascular leakage. Retinal development in the conditional VEGF knockout mice was analysed by examining retinal and choroidal vasculatures and retinal morphology and function. Ischaemia-induced retinal neovascularization and vascular leakage in the conditional VEGF knockout mice were analysed with fluorescein angiography, quantification of proliferative neovascular cells, immunohistochemistry, and immunoblotting using an oxygen-induced retinopathy model. Our results demonstrated that disruption of Müller cell-derived VEGF resulted in no apparent defects in retinal and choroidal vasculatures and retinal morphology and function, significant inhibition of the ischaemia-induced retinal neovascularization and vascular leakage, and attenuation of the ischaemia-induced breakdown of the blood-retina barrier. These results suggest that the retinal Müller cell-derived VEGF is a major contributor to ischaemia-induced retinal vascular leakage and pre-retinal and intra-retinal neovascularization. The observation that a significant, but not complete, reduction of VEGF in the retina does not cause detectable retinal degeneration suggests that appropriate doses of anti-VEGF agents may be important to the safe treatment of retinal vascular diseases.

Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

“…These cells develop and maintain a close contact with both superficial vessels and deeper capillaries via their multiple end-feet (Newman and Reichenbach, 1996) and have been implicated in angiogenesis by virtue of their ability to produce angiogenic substances in response to hypoxia (Pierce et al, 1995;Stone et al, 1995;Robbins et al, 1997). However, as the Müller cell-specific deletion of VEGF-A inhibited neovascularization in a mouse model of oxygen-induced retinopathy without affecting physiological vascularization or retinal morphology (Bai et al, 2009), it was assumed that Müller cells play a greater role in proliferative retinopathy than physiological angiogenesis. In our study, the deletion of the sEH in Müller cells clearly affected endothelial cell proliferation as well as Notch signaling and tip cell filopodia formation in mice, indicating that Müller cells make a more important contribution to retinal angiogenesis than generally appreciated.…”

Elevated cell proliferation and VEGF production by high-glucose conditions in Müller cells involve XIAP

“…9,10 Moreover, increased VEGF expression in Mü ller cells under hyperglycemic conditions is one of the major contributors to pathological intraocular neovascularization. 11,12 Therefore, exposing the potential mechanism of glucoseinduced VEGF expression in Mü ller cells is essential to reveal the underlying neovascularization in diabetic retinopathy.…”

Ischaemia-induced retinal neovascularisation and diabetic retinopathy in mice with conditional knockout of hypoxia-inducible factor-1 in retinal Müller cells

“…Retinal Müller cells are the principal supporting cells in the neural retina and participate in retinal angiogenesis, neural protection and other physiological functions [15,16]. Recent studies have indicated that HIF-1α is produced in all of the retinal layers [17].…”