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Therapies targeting VEGF have proven only modestly effective for the treatment of proliferative sickle cell retinopathy (PSR), the leading cause of blindness in patients with sickle cell disease. Here, we shift our attention upstream from the genes that promote retinal neovascularization (NV) to the transcription factors that regulate their expression. We demonstrated increased expression of HIF-1[alpha] and HIF-2[alpha] in the ischemic inner retina of PSR eyes. Although both HIFs participated in promoting VEGF expression by hypoxic retinal Muller cells, HIF-1 alone was sufficient to promote retinal NV in mice, suggesting that therapies targeting only HIF-2 would not be adequate to prevent PSR. Nonetheless, administration of a HIF-2-specific inhibitor currently in clinical trials (PT2385) inhibited NV in the oxygen-induced retinopathy (OIR) mouse model. To unravel these discordant observations, we examined the expression of HIFs in OIR mice and demonstrated rapid but transient accumulation of HIF-1[alpha] but delayed and sustained accumulation of HIF- 2[alpha]; simultaneous expression of HIF-1[alpha] and HIF-2[alpha] was not observed. Staggered HIF expression was corroborated in hypoxic adult mouse retinal explants but not in human retinal organoids, suggesting that this phenomenon may be unique to mice. Using pharmacological inhibition or an in vivo nanoparticle-mediated RNAi approach, we demonstrated that inhibiting either HIF was effective for preventing NV in OIR mice. Collectively, these results explain why inhibition of either HIF-1[alpha] or HIF-2[alpha] is equally effective for preventing retinal NV in mice but suggest that therapies targeting both HIFs will be necessary to prevent NV in patients with PSR., Introduction Several multicenter randomized controlled clinical trials have demonstrated the benefit of monthly (or bimonthly) injections with biological molecules directed against the vasoactive mediator VEGF to treat macular edema in [...]

Purpose: This study evaluates the efficacy and patient satisfaction of intravitreal conbercept (IVC) as adjunctive treatment before panretinal photocoagulation (PRP) for Chinese proliferative diabetic retinopathy (PDR) with or without clinically significant macular edema. Methods: We enrolled 94 patients and categorized them into 2 groups: eyes that received PRP with single-dose IVC (0.5 mg/0.05 mL) 1 week before PRP (Plus group) or PRP only (PRP group). We measured the central macular thickness (CMT) by optical coherence tomography and best-corrected visual acuity. Satisfaction of PRP after 3 months was evaluated by a satisfaction questionnaire. Results: Single-dose IVC 1 week before PRP significantly increased the PRP completion rate and satisfaction of treatment after 3 months in PDR patients. The average CMT significantly decreased in the Plus group but increased in the PRP group. No average visual changes were detected in the Plus group, but significant average visual loss was detected in the PPR group. The most important factors that determined satisfaction were the PRP completion rate in the short term and better vision gain after PRP. Conclusions: IVC is a promising adjunctive treatment to PRP in the treatment of PDR. Single-dose IVC 1 week before PRP was suggested to improve PRP completion rate and patient satisfaction in the short term. [ABSTRACT FROM AUTHOR]

Purpose: To determine the effect of three-month diabetes on the retinal ganglion cell (RGC) morphology and density. Methods: Experimental diabetes was induced in Sprague-Dawley rats by intraperitoneal injection of streptozotocin (STZ). Retinas from three-month diabetic and age-matched control rats were harvested, and immunohistochemistry with monoclonal anti-Thy-1 antibody was carried out for calculating RGC density. Random RGC labeling with gene gun propelled lipophilic fluorescent dye, DiI, coated particles (DiOlistic method) was done for detailed RGC classification, dendritic field, and soma size measurement. Results: The number of Thy1-labeled RGCs in the three-month diabetic rats was significantly reduced compared with that in the age-matched control. Obvious RGC morphology changes were observed, and the number of RGCs that could not be classified was significantly greater in the diabetic retinas. Among those well-classified RGCs, cells with enlarged dendritic fields were more frequently seen in the RGA group (401±86um, n = 59, P < 0.001), but the soma sizes were unchanged from the controls (P > 0.05). For cells in the groups of RGB and RGC, no significant changes in the dendritic fields and soma sizes were found (P > 0.05). Conclusions: In the three-month STZ-induced diabetic rat, retinal ganglion cell loss is associated with morphology change. The surviving RGCs in the diabetic retina, especially those in RGA group, show significant dendritic field enlargement. This plasticity of the surviving RGC dendrites may represent a compensatory response to the overall loss of RGCs in diabetes. [ABSTRACT FROM AUTHOR]

For patients with proliferative diabetic retinopathy (PDR) who do not respond adequately to pan-retinal laser photocoagulation (PRP) or anti-vascular endothelial growth factor (VEGF) therapies, we hypothesized that vascular cells within neovascular tissue secrete autocrine/paracrine angiogenic factors that promote disease progression. To identify these factors, we performed multiplex ELISA angiogenesis arrays on aqueous fluid from PDR patients who responded inadequately to anti-VEGF therapy and/or PRP and identified plasminogen activator inhibitor-1 (PAI-1). PAI-1 expression was increased in vitreous biopsies and neovascular tissue from PDR eyes, limited to retinal vascular cells, regulated by the transcription factor hypoxia-inducible factor (HIF)-2α, and necessary and sufficient to stimulate angiogenesis. Using a pharmacologic inhibitor of HIF-2α (PT-2385) or nanoparticle-mediated RNA interference targeting Pai1 , we demonstrate that the HIF-2α/PAI-1 axis is necessary for the development of retinal neovascularization in mice. These results suggest that targeting HIF-2α/PAI-1 will be an effective adjunct therapy for the treatment of PDR patients.

Purpose: This retrospective study investigated the patterns and risk factors of progression of myopic traction maculopathy (MTM) of fellow eyes after pars plana vitrectomy (PPV) of primary eyes., Methods: The study population comprised 153 patients with MTM in both myopic eyes who sequentially underwent PPV (2006-2021). Observation periods were from PPV of the primary eye (baseline) to PPV of the fellow (end). MTM was graded based on optical coherence tomography (OCT) images and the ATN (atrophy [A], traction [T], and neovascularization [N]) system. An increase in T grade was considered MTM progression., Results: MTM progressed in 43.8% of fellow eyes during 34.57 ± 34.08 months. The progression of fellow eyes correlated with T grade of primary eyes (P < 0.001). Risk factors for the progression of MTM in fellow eyes were primary eyes in T4-T5, age at baseline <60 years, and fellow eyes with partial posterior vitreous detachment (PVD; P < 0.001, P = 0.042, and P = 0.002, respectively). Fellow eyes in T1/T2 at baseline progressed faster compared with those in T0 (P < 0.001); the annual rate of progression to T3-T5 of the T0 (T1-T2) groups was 9.98% (24.59%)., Conclusions: Risk factors for the progression of MTM in fellow eyes included PPV when relatively young, primary eye at high T grade, and partial PVD of the fellow eye. Personalized follow-up for fellow eyes should be based on the severity of MTM of both eyes.

Purpose: We investigated the protective effects of HO-1, induced by hemin, in the retinas of streptozotocin (STZ)-induced diabetic rats, and document the possible anti-inflammatory, anti-apoptotic, and anti-proliferative mechanisms underlying the protection., Methods: Sprague-Dawley (SD) rats were induced to diabetes by intraperitoneal injection of STZ (60 mg/kg). Later, some of the rats were given intraperitoneal injections of hemin (20 mg/kg) to induce expression of HO-1. The protective effects of hemin were evaluated by examining the hemoglobin concentration (Hb) and the glycosylated hemoglobin (HbA1c) level of blood from the rats, further calculating the numbers of TUNEL positive cells in retinal ganglion cell (RGC) layer and diI-labeled RGCs. We also documented the expressions of HO-1, HIF-1α, SOD-1, VEGF, p53, and bcl-2 by Western blot analysis and real-time quantitative PCR. Expressions of Nrf2, tERK 1/2, and pERK 1/2 were detected only by Western blot analysis. HO-1, Nrf2, pERK, and GFAP proteins were detected by immunofluorescence., Results: The Hb level was higher in hemin-treated rat blood than nontreated diabetic group, while the HbA1c level was lower. Hemin significantly activated HO-1 expression in the retinas of diabetic rats, combined with accordant changes of Nrf2/pERK protein expression, and upregulated the expression of GFAP in retina. Retinal ganglion cells displayed greater sensitivity to apoptosis when the HO-1 level was lower. Overexpression of HO-1 was associated with an increase in the activation of SOD-1 and bcl-2, and a decrease of the expression of HIF-1α, VEGF, and p53., Conclusions: HO-1 is an important positive modulator of the Nrf2/ERK-related signaling. Overexpression of HO-1 by hemin induction protected retinal ganglion cells in diabetic retinopathy through anti-inflammatory, anti-apoptotic, and anti-proliferative effects.

Purpose: We explored the relationship between the renin-angiotensin system (RAS) and aquaporins (AQP1 and AQP4 in Müller glia and astrocytes) in diabetic retinopathy (DR) with and without systemic hypertension., Methods: Diabetes was induced in spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats by intraperitoneal injections of streptozotocin. The diabetic and control non-diabetic rats were assigned randomly to receive no anti-hypertension treatment, or to be treated with the angiotensin II receptor blocker (ARB), valsartan (40 mg/kg/d) or the beta-blocker, metoprolol (50 mg/kg/day). Eight weeks later, retinas were evaluated by immunohistochemistry and Western blot to detect changes in the expression of AQP1, AQP4, and glial fibrillary acidic protein (GFAP)., Results: Hypertension increased expression of glial GFAP and AQP4 (P < 0.01), but not AQP1 (P > 0.05) in diabetic rats. Valsartan and metoprolol decreased GFAP, AQP1, and AQP4 expression in diabetic SHR rats (P < 0.01). Valsartan decreased GFAP and AQP1 expression in diabetic WKY rats (P < 0.01), while metoprolol did not., Conclusions: Activation of Müller glia and astrocytes was involved in the mechanism by which systemic hypertension affects DR. AQPs and macroglia were linked to changes in the RAS in DR. Changes in aquaporin expression in DR were increased by hypertension. This provides additional support for the early use of an ARB in the treatment of DR, especially in cases with retinal edema.

Purpose: Vascular endothelial growth factor (VEGF) is one of the major factors promoting diabetic retinopathy (DR). A better understanding of the signaling pathway in VEGF regulation is of clinical importance to identify more precise therapeutic targets for diabetic retinopathy. The ERK1/2 signaling pathway has been shown to play a key role in some oncoma and hematologic diseases by mediating VEGF release. This research was conducted to determine whether the ERK1/2 signaling pathway also plays a major role in VEGF release in DR development., Methods: One hundred Sprague-Dawley (SD) rats were induced to diabetes by streptozotocin (STZ) injection and monitored at several time points (1, 2, 3, 4, 8, and 12 weeks) for ERK1/2 phosphorylation, Activator protein (AP)-1 activity and concentration, and VEGF protein and mRNA expression, using immunohistochemical and biochemical methods. RESULTS. The ERK1/2 signaling pathway was rapidly activated 1 week after diabetes was induced. AP-1, the downstream transcription factor of ERK1/2, was also activated, and VEGF became highly regulated in a similar trend. U0126, an inhibitor of ERK1/2, also downregulated VEGF expression, in addition to ERK1/2 and AP-1 activity., Conclusions: ERK1/2 signaling pathway is involved in VEGF release in diabetic rat retina; therefore, ERK1/2 may be a potential therapeutic target of DR.

Purpose: To investigate the variation of macular light sensitivity (MLS) in myopic Chinese adults by using microperimetry., Methods: MLS was recorded with the MP1 microperimeter (Nidek Technologies, Padova, Italy) in eyes affected by various degrees of myopia. Subjects were divided into group A (18-30 years) and group B (31-60 years). Subjects in both age groups were further divided based on refractive status: (1) high myopia (spherical equivalent, SE<-6.00 D); (2) low to moderate myopia (-6.00 D