An anti-angiogenic state in mice and humans with retinal photoreceptor cell degeneration

Abstract

Abnormal angiogenesis accompanies many pathological conditions including cancer, inflammation, and eye diseases. Proliferative retinopathy because of retinal neovascularization is a leading cause of blindness in developed countries. Another major cause of irreversible vision loss is retinitis pigmentosa, a group of diseases characterized by progressive photoreceptor cell degeneration. Interestingly, anecdotal evidence has long suggested that proliferative diabetic retinopathy is rarely associated clinically with retinitis pigmentosa. Here we show that neonatal mice with classic inherited retinal degeneration (Pdeb rd1 /Pdeb rd1 ) fail to mount reactive retinal neovascularization in a mouse model of oxygeninduced proliferative retinopathy. We also present a comparable human paradigm: spontaneous regression of retinal neovascularization associated with long-standing diabetes mellitus occurs when retinitis pigmentosa becomes clinically evident. Both mouse and human data indicate that reactive retinal neovascularization either fails to develop or regresses when the number of photoreceptor cells is markedly reduced. Our findings support the hypothesis that a functional mechanism underlying this anti-angiogenic state is failure of the predicted up-regulation of vascular endothelial growth factor, although other growth factors may also be involved. Preventive and therapeutic strategies against both proliferative and degenerative retinopathies may emerge from this work.

Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch

“…1 A-C). This vascular response was consistent with previous reports (17)(18)(19), and with the noteworthy increase in Vegfa expression (ANOVA, P = 1.83 × 10 −15 ) that was apparent 12 h after the animals were returned to room air (Fig. 1D).…”

“…The O 2 -induced retinal neovascularization model (17)(18)(19) has been widely used to study the molecular mechanisms of blood vessel formation during relative hypoxia. Here, we used this model to address the putative role of miR-17 family members in the early steps of the angiogenic switch (Fig.…”

“…Experiments were performed in duplicate with two independent O 2 chambers. On average, five mice (i.e., 10 retinas) were used for each time point (0, 6, or 12 h) in each chamber as described (17)(18)(19). Retinas were immediately dissected under a stereomicroscope and kept in RNAlater (Ambion) at 4°C until the RNA was extracted.…”

“…Therefore, by simultaneously targeting these two key genes, miR-17 family members could, in theory, be important concerted regulators of angiogenesis. As proof of concept, we tested this hypothesis in the experimental mouse model of retinopathy of prematurity (ROP), where Vegfa seems to be a pivotal factor that modulates the angiogenic switch (17)(18)(19). In this model, the expression of retinal Vegfa mRNA increases sharply 12 h after the animals are returned from 75% oxygen (O 2 ) back to room air (∼21% O 2 ), a process that induces a relative hypoxic condition and leads to retinal neovascularization in the subsequent 9 d (17)(18)(19).…”

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

“…This suggests that RdCVF has a role in protection against hyperoxia, of significance given that oxygen toxicity is considered to be a major factor in triggering cone photoreceptor death and thus the onset of severe blindness in the end stages of RP. 27 However, the mechanism of cell loss itself remains ambiguous with a marked absence of TUNEL-positive cells in the retinas of the knockout mice at 3 and 12 months of age. TUNEL staining, although a classic marker for apoptosis may not be reliable in some forms of RD, as the highly efficient autophagocytic mechanisms inherent to retinal function may achieve a rapid clearance of cell debris with each wave of cell loss.…”