MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by post-transcriptional inhibition of mRNA translation. Dysregulation of miRNAs, including circulating miRNAs, has been reported to play an important role in the development of various diseases, including fibrotic diseases. Aberrant expression of miRNAs in the vitreous humor of vitreoretinal diseased eyes has been reported. However, the expression pattern of miRNAs present in the vitreous humor of proliferative vitreoretinal disease (PVD) patients, including proliferative diabetic retinopathy (PDR), and proliferative vitreoretinopathy (PVR), remains unknown. To investigate the factors important for the development of PVD, we characterized the miRNAs present in the vitreous humor of PVD patients and analyzed the expression profiles of 377 miRNAs using quantitative polymerase chain reaction-based miRNA arrays. The expression of a specific subset of miRNAs, previously reported to be associated with the development of angiogenesis and fibrosis, was significantly altered in the vitreous of PVD patients. Among these miRNAs, we identified miR-21 as a candidate fibrotic miRNA with an important role in the pathogenesis of PVD. Increased miR-21 levels in the vitreous were associated with retinal fibrosis, including PVR and PDR. Because epithelial-mesenchymal transition (EMT) of retinal pigment epithelial cells (RPECs) plays a critical role in retinal fibrosis, the expression of miR-21 in human RPECs was determined. Its expression in RPECs was induced by transforming growth factor-β, a key growth factor involved in fibrogenesis, and was enhanced by high glucose culture conditions, suggesting that miR-21 expression positively correlates with disease progression. Gain- and loss-of-function studies revealed that miR-21 promoted cell proliferation and migration of ARPE-19 cells without affecting EMT-related gene expression. Together, our studies have identified miR-21 as a potential disease-modifying miRNA in the vitreous humor that is involved in the development of retinal fibrosis and may be a novel marker of PVD.
Retinal neovascularization (NV), a leading cause of vision loss, results from localized hypoxia that stabilizes the hypoxia-inducible transcription factors HIF-1α and HIF-2α, enabling the expression of angiogenic factors and genes required to maintain homeostasis under conditions of oxygen stress. HIF transcriptional activity depends on the interaction between its intrinsically disordered C-terminal domain and the transcriptional coactivators CBP/p300. Much effort is currently directed at disrupting protein–protein interactions between disease-associated transcription factors like HIF and their cellular partners. The intrinsically disordered protein CITED2, a direct product of HIF-mediated transcription, functions as a hypersensitive negative regulator that attenuates the hypoxic response by competing allosterically with HIF-1α for binding to CBP/p300. Here, we show that a peptide fragment of CITED2 is taken up by retinal cells and efficiently regulates pathological angiogenesis in murine models of ischemic retinopathy. Both vaso-obliteration (VO) and NV were significantly inhibited in an oxygen-induced retinopathy (OIR) model following intravitreal injection of the CITED2 peptide. The CITED2 peptide localized to retinal neurons and glia, resulting in decreased expression of HIF target genes. Aflibercept, a commonly used anti-VEGF therapy for retinal neovascular diseases, rescued NV but not VO in OIR. However, a combination of the CITED2 peptide and a reduced dose of aflibercept significantly decreased both NV and VO. In contrast to anti-VEGF agents, the CITED2 peptide can rescue hypoxia-induced retinal NV by modulating the hypoxic response through direct competition with HIF for CBP/p300, suggesting a dual targeting strategy for treatment of ischemic retinal diseases and other neovascular disorders.
PurposeThe purpose of this study was to determine the clinical efficacy of low-frequency intravitreal ranibizumab to treat macular edema due to retinal vein occlusion (RVO).Patients and methodsThis was a retrospective examination of cases that received intravitreal ranibizumab for untreated RVO over a period of 12 months. Instead of the conventional three monthly injections, injections were given once during the introductory period. If the recurrence of macular edema was diagnosed during the monthly visit, additional injections were given as needed. There were 21 eyes of 21 patients with branch RVO (BRVO) and ten eyes of ten patients with central RVO (CRVO). The parameters examined included the number of injections over the 12-month period, improvements in best-corrected visual acuity (BCVA), and the central macular thickness (CMT). For BRVO, preinjection parameters that had an effect on the prognosis of BCVA after the 12-month period were also examined.ResultsThe total mean number of injections over the 12-month period was 3.4 for CRVO and 2.1 for BRVO. For CRVO, the BCVA in log minimum angular resolution changed from a preinjection value of 0.80 to 0.55 at 12 months. For BRVO, the change was from 0.51 to 0.30. For all diseases, BCVA improved after 12 months compared with the preinjection values (P<0.05). There was improvement in the CMT, and the CRVO changed from 765.0 μm at preinjection to 253.5 μm 12 months later. BRVO changed from 524.1 to 250.1 μm, and pre-injection BCVA was associated with a prognosis of visual acuity after 12 months of the initial injection (P=0.0485).ConclusionEven with a low number of injections during the introductory period, there were still improvements in both visual acuity and CMT in RVO patients after 12 months, indicating that it was an effective treatment.
Disruption of the neurovascular unit (NVU) underlies the pathophysiology of various CNS diseases. One strategy to repair NVU dysfunction uses stem/progenitor cells to provide trophic support to the NVU’s functionally coupled and interdependent vasculature and surrounding CNS parenchyma. A subset of endothelial progenitor cells, endothelial colony-forming cells (ECFCs) with high expression of the CD44 hyaluronan receptor (CD44 hi ), provides such neurovasculotrophic support via a paracrine mechanism. Here, we report that bioactive extracellular vesicles from CD44 hi ECFCs (EVs hi ) are paracrine mediators, recapitulating the effects of intact cell therapy in murine models of ischemic/neurodegenerative retinopathy; vesicles from ECFCs with low expression levels of CD44 (EVs lo ) were ineffective. Small RNA sequencing comparing the microRNA cargo from EVs hi and EVs lo identified candidate microRNAs that contribute to these effects. EVs hi may be used to repair NVU dysfunction through multiple mechanisms to stabilize hypoxic vasculature, promote vascular growth, and support neural cells.
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