Antioxidant or neurotrophic factor treatment preserves function in a mouse model of neovascularization-associated oxidative stress

Abstract

In several disease states, abnormal growth of blood vessels is associated with local neuronal degeneration. This is particularly true in ocular diseases such as retinal angiomatous proliferation (RAP) and macular telangiectasia (MacTel), in which, despite the absence of large-scale leakage or hemorrhage, abnormal neovascularization (NV) is associated with local neuronal dysfunction. We describe here a retinal phenotype in mice with dysfunctional receptors for VLDL (Vldlr -/-mice) that closely resembles human retinal diseases in which abnormal intra-and subretinal NV is associated with photoreceptor cell death. Such cell death was evidenced by decreased cone and, to a lesser extent, rod opsin expression and abnormal electroretinograms. Cell death in the region of intraretinal vascular abnormalities was associated with an increased presence of markers associated with oxidative stress. Oral antioxidant supplementation protected against photoreceptor degeneration and preserved retinal function, despite the continued presence of abnormal intra-and subretinal vessels. What we believe to be novel, Müller cell-based, virally mediated delivery of neurotrophic compounds specifically to sites of NV was also neuroprotective. These observations demonstrate that neuronal loss secondary to NV can be prevented by the use of simple antioxidant dietary measures or cell-based delivery of neurotrophic factors, even when the underlying vascular phenotype is not altered.

Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae

“…We therefore hypothesize that SRF-controlled expression of thrombospondin is required in adult retinal vessels to inhibit pathological EC proliferation, thereby providing an explanation for both the NV phenotype we observed upon adult-stage SRF depletion and the overlapping phenotypic characteristics with the MacTel model of Vldlr -/-mice. As shown in the Vldlr -/-model, constitutive VLDLR deficiency did not severely affect postnatal development of the primary plexus, but rather caused abnormal intraretinal vessel growth during deep plexi formation (9), which suggests that VLDLR functions in maintaining homeostasis of primarily deep retinal vessels. Our phenotype of intraretinal NV upon adult SRF depletion and the hypothesized impairment of VLDLR signaling by associated thrombospondin deficiency are fully consistent with the defects displayed by Vldlr -/-mice.…”

“…The latter displayed distortions in INL and ONL layering, local thinning of the ONL, disruption of photoreceptors associated with reduced expression of Opn1 and Rho, and rupture of the RPE with RPE cells enveloping the NV structures. Collectively, these abnormalities represent characteristic features of the human NV AMD subtypes RAP (7) and MacTel (8)(9)(10). Very similar phenotypic features were displayed by mice deficient for VLDLR, a component of reelin signaling exerting inhibitory effects on EC proliferation (9, 40-43).…”

“…Postnatal EC ablation of either SRF or MRTFs led to severe developmental vessel growth defects, resembling major characteristics of inherited human retinal pathologies such as ROP and FEVR, including ND (3). Interestingly, we found that EC-specific deletion of Srf in adult mice triggered unwarranted intraretinal NV, reminiscent of the human NV AMD subtypes RAP and MacTel (7,10), as well as the RAP/MacTel animal model deficient for the VLDL receptor (VLDLR; encoded by Vldlr) (9). Moreover, our study investigated EC VEGF signaling mechanisms in vitro and identified MRTF-SRF activation downstream of VEGF.…”

“…NV AMD, which represents approximately 10% of all AMD yet accounts for nearly 90% of all AMD-associated vision losses (6), displays either choroidal NV or, more rarely, intraretinal NV. The latter is found in the manifestations of retinal angiomatous proliferation (RAP) (7) and macular telangiectasia (MacTel) (8)(9)(10).…”

La conception de vecteurs adaptés à la thérapie génique oculaire

“…ShH10 [35] AAV2 [41] AAV9 [22] ShH13 [42] Photorécepteurs AAV2-7m8 [32] AAV2-4YF [31] AAV2 [43] AAV5 [43] AAV7 [22] AAV8 [22] AAV9 [22] Épithélium pigmentaire…”