RESUMO
Diabetic retinopathy (DR) is characterized as a microvascular disease. Nonproliferative diabetic retinopathy (NPDR) presents with alterations in retinal blood flow and vascular permeability, thickening of the basement membrane, loss of pericytes, and formation of acellular capillaries. Endothelial-mesenchymal transition (EndMT) of retinal microvessels may play a critical role in advancing NPDR. Melatonin, a hormone primarily secreted by the pineal gland, is a promising therapeutic for DR. This study explored the EndMT in retinal microvessels of NPDR and its related mechanisms. The effect of melatonin on the retina of diabetic rats was evaluated by electroretinogram (ERG) and histopathologic slide staining. Furthermore, the effect of melatonin on human retinal microvascular endothelial cells (HRMECs) was detected by EdU incorporation assay, scratch assay, transwell assay, and tube formation test. Techniques such as RNA-sequencing, overexpression or knockdown of target genes, extraction of cytoplasmic and nuclear protein, co-immunoprecipitation (co-IP), and multiplex immunofluorescence facilitated the exploration of the mechanisms involved. Our findings reveal, for the first time, that melatonin attenuates diabetic retinopathy by regulating EndMT of retinal vascular endothelial cells via inhibiting the HDAC7/FOXO1/ZEB1 axis. Collectively, these results suggest that melatonin holds potential as a therapeutic strategy to reduce retinal vascular damage and protect vision in NPDR.
Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Células Endoteliais , Histona Desacetilases , Melatonina , Homeobox 1 de Ligação a E-box em Dedo de Zinco , Melatonina/farmacologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/patologia , Animais , Ratos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Histona Desacetilases/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Humanos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Masculino , Proteína Forkhead Box O1/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Ratos Sprague-Dawley , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Retina/metabolismo , Retina/efeitos dos fármacos , Retina/patologia , Transição Endotélio-MesênquimaRESUMO
BACKGROUND: Diabetic retinopathy (DR), the principal cause of acquired blindness among the working-age population, is the most frequent microvascular complication of diabetes. Although metabolic disorders are hypothesized to play a role in its pathogenesis, the underlying mechanism remains largely elusive. METHODS: To elucidate the mechanism, we initially compared metabolite profiles of vitreous fluid between 23 patients with DR and 12 non-diabetic controls using liquid chromatography/tandem mass spectrometry, identifying the distinct metabolite indoxyl sulfate (IS). Subsequently, streptozotocin (STZ)-induced diabetic and IS-injected rat models were established to examine the effects of IS on retinal microvasculature. RNA sequencing was conducted to identify potential regulatory mechanisms in IS-treated human retinal endothelial cells (HREC). Finally, target gene knockdown in HREC and treatment of IS-injected rats with inhibitors (targeting IS production or downstream regulators) were employed to elucidate the detailed mechanisms and identify therapeutic targets for DR. RESULTS: Metabolomics identified 172 significantly altered metabolites in the vitreous humor of diabetics, including the dysregulated tryptophan metabolite indoxyl sulfate (IS). IS was observed to breach the blood-retinal barrier and accumulate in the intraocular fluid of diabetic rats. Both in vivo and in vitro experiments indicated that elevated levels of IS induced endothelial apoptosis and disrupted cell junctions. RNA sequencing pinpointed prostaglandin E2 (PGE2) synthetase-cyclooxygenase 2 (COX-2) as a potential target of IS. Validation experiments demonstrated that IS enhanced COX-2 expression, which subsequently increased PGE2 secretion by promoting transcription factor EGR1 binding to COX-2 DNA following entry into cells via organic anion transporting polypeptides (OATP2B1). Furthermore, inhibition of COX-2 in vivo or silencing EGR1/OATP2B1 in HREC mitigated IS-induced microcapillary damage and the activation of COX-2/PGE2. CONCLUSION: Our study demonstrated that indoxyl sulfate (IS), a uremic toxin originating from the gut microbiota product indole, increased significantly and contributed to retinal microvascular damage in diabetic retinopathy (DR). Mechanistically, IS impaired retinal microvascular integrity by inducing the expression of COX-2 and the production of PGE2. Consequently, targeting the gut microbiota or the PGE2 pathway may offer effective therapeutic strategies for the treatment of DR.
Assuntos
Ciclo-Oxigenase 2 , Diabetes Mellitus Experimental , Retinopatia Diabética , Dinoprostona , Indicã , Microvasos , Retinopatia Diabética/patologia , Retinopatia Diabética/metabolismo , Animais , Humanos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Masculino , Microvasos/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Ratos Sprague-Dawley , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Vasos Retinianos/efeitos dos fármacos , Ratos , Pessoa de Meia-Idade , Retina/patologia , Retina/metabolismo , Retina/efeitos dos fármacos , Apoptose/efeitos dos fármacosRESUMO
In patients with Alzheimer's disease (AD) and in animal models, the increased accumulation of amyloid ß (Aß) in retinal blood vessels strongly correlates with brain amyloid deposits and cognitive decline. The accumulation of Aß in blood vessels may result from impaired transcytosis and a dysfunctional ocular glymphatic system in AD. High-dose fish oil (FO) supplementation has been shown to significantly change the expression of major facilitator superfamily domain-containing protein 2a (Mfsd2a), a key regulator of transcytosis, and Aquaporin 4 (Aqp4), an essential component of the glymphatic system in the retinas of WT mice. We examined the expression of Mfsd2a and Aqp4 in the retinas of 4-month-old 5xFAD female mice supplemented with high-dose FO for three weeks. There was a significant increase in Mfsd2a expression in 5xFAD retinas supplemented with FO compared to control 5xFAD mice. Additionally, the increase in Aqp4 expression observed in 4-month-old 5xFAD retinas, indicative of an impaired glymphatic system, was significantly decreased. Simultaneously, Aß accumulation in 5xFAD retinal blood vessels was reduced following FO supplementation. These findings suggest that high-dose FO supplementation could serve as an adjunct in developing new treatments aimed at improving the regulation of transcytosis or the function of the glymphatic system in the AD retina.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Aquaporina 4 , Suplementos Nutricionais , Modelos Animais de Doenças , Óleos de Peixe , Camundongos Transgênicos , Vasos Retinianos , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Aquaporina 4/metabolismo , Aquaporina 4/genética , Peptídeos beta-Amiloides/metabolismo , Camundongos , Feminino , Vasos Retinianos/metabolismo , Vasos Retinianos/efeitos dos fármacos , Óleos de Peixe/farmacologia , Óleos de Peixe/administração & dosagem , Simportadores/metabolismo , Simportadores/genética , HumanosRESUMO
Diabetic retinopathy (DR) is a prevalent complication of diabetes, often resulting in vision loss and blindness. Existing treatments primarily aim to control blood sugar levels and inhibit angiogenesis. However, current therapies for DR, such as anti-VEGF and laser photocoagulation, are frequently invasive, and can cause adverse side effects. Consequently, there is a critical need for new preventive therapeutics to address DR more effectively. This study aimed to examine the therapeutic potential of a histamine H4 receptor (HRH4) antagonist as a preventive treatment for DR in mice. A mouse model of DR was established by intraperitoneally injecting 200 mg/kg of streptozotocin (STZ). Immune cell infiltration into the retina of mice with STZ-induced diabetes was measured using fluorescence-activated cell sorting (FACS) 12 weeks after STZ injection. The preventive effects of the HRH4 antagonist on inflammation and pathological retinal vessel leakage were determined in a mouse model of DR. Infiltration of HRH4-expressing macrophages increased in the retina of mice with STZ-induced DR. The HRH4 antagonist prevented macrophage infiltration and retinal vascular leakage to prevent STZ-induced DR in mice without causing any retinal toxicity. The infiltration of macrophages increased in the retina of mice with STZ-induced diabetes through HRH4, indicating that HRH4 is potentially a novel preventative therapeutic target in DR. These findings suggest that targeting HRH4 is a promising strategy for the prevention and treatment of DR.
Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Receptores Histamínicos H4 , Animais , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/prevenção & controle , Retinopatia Diabética/patologia , Retinopatia Diabética/etiologia , Receptores Histamínicos H4/antagonistas & inibidores , Camundongos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Masculino , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/uso terapêutico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Retina/patologia , Retina/efeitos dos fármacos , Retina/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/patologiaRESUMO
Purpose: In response to hypoxia, sympathetic fibers to the retina activate ß-adrenoceptors (ß-ARs) that play an important role in the regulation of vascular and neuronal functions. We investigated the role of ß3-AR using the mouse model of oxygen-induced retinopathy (OIR). Methods: Mouse pups were exposed to 75% oxygen at postnatal day 7 (PD7) followed by a return to room air at PD12. The ß3-AR preferential agonist BRL37344 was subcutaneously administered once daily at different times after the return to room air. At PD17, the OIR mice underwent flash and pattern electroretinogram. After sacrifice, retinal wholemounts were used for vessel staining or immunohistochemistry for astrocytes, Müller cells, or retinal ganglion cells (RGCs). In retinal homogenates, the levels of markers associated with neovascularization (NV), the blood-retinal barrier (BRB), or astrocytes were determined by western blot, and quantitative reverse-transcription polymerase chain reaction was used to assess ß3-AR messenger. Administration of the ß3-AR antagonist SR59230A was performed to verify BRL37344 selectivity. Results: ß3-AR expression is upregulated in response to hypoxia, but its increase is prevented by BRL37344, which counteracts NV by inhibiting the pro-angiogenic pathway, activating the anti-angiogenic pathway, recovering BRB-associated markers, triggering nitric oxide production, and favoring revascularization of the central retina through recovered density of astrocytes that ultimately counteracts NV in the midperiphery. Vasculature rescue prevents dysfunctional retinal activity and counteracts OIR-associated retinal ganglion cell loss. Conclusions: ß3-AR has emerged as a crucial intermediary in hypoxia-dependent NV, suggesting a role of ß3-AR agonists in the treatment of proliferative retinopathies.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Modelos Animais de Doenças , Eletrorretinografia , Camundongos Endogâmicos C57BL , Oxigênio , Receptores Adrenérgicos beta 3 , Neovascularização Retiniana , Animais , Camundongos , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/prevenção & controle , Neovascularização Retiniana/patologia , Oxigênio/toxicidade , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Receptores Adrenérgicos beta 3/metabolismo , Animais Recém-Nascidos , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Etanolaminas/farmacologia , Vasos Retinianos/efeitos dos fármacos , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/tratamento farmacológico , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Imuno-Histoquímica , AngiogêneseRESUMO
BACKGROUND: The study was designed to investigate microvascular and morphological changes in retinal vein occlusion (RVO) using multimodal imaging after intravitreal ranibizumab (IVR) with or without triamcinolone acetonide (IVTA) injections. METHODS: This was a retrospective and observational study. Fifty patients (52 eyes) diagnosed with RVO were enrolled. Best corrected visual acuity (BCVA), ophthalmoscopy, fundus fluorescein angiography (FFA), spectral domain optical coherence tomography (SDOCT), and optical coherence tomography angiography (OCTA) were employed sequentially both before treatment and at the last visit after treatment. RESULTS: The mean logMAR VAs in BRVO eyes decreased significantly after treatment (P = 0.029). OCTA showed there was a significant difference in foveal avascular zone (FAZ) in BRVO eyes (P = 0.024), superificial foveal vessel density in both CRVO (P = 0.0004) and BRVO eyes (P = 0.02155). OCT showed the foveal thickness had significant differences after treatment in both CRVO (P < 0.0001) and BRVO eyes (P = 0.0001). BCVA was associated most commonly with ellipsoid zone integrity (P = 0.022). The BCVA in eyes treated with IVR and IVTA was significantly decreased compared with IVR only in BRVO group (P = 0.021). However, the combination of IVR + IVTA significantly improved intraocular pressure (IOP) compared with IVR only in BRVO group (P = 0.037). CONCLUSION: Both IVR and IVR + IVTA can significantly improve the central vision, macular structure, and functions in BRVO group. Simultaneous IVR with IVTA can significantly increase BCVA compared with IVR only in BRVO group.
Assuntos
Inibidores da Angiogênese , Angiofluoresceinografia , Glucocorticoides , Injeções Intravítreas , Imagem Multimodal , Ranibizumab , Oclusão da Veia Retiniana , Tomografia de Coerência Óptica , Triancinolona Acetonida , Acuidade Visual , Humanos , Oclusão da Veia Retiniana/tratamento farmacológico , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/fisiopatologia , Estudos Retrospectivos , Masculino , Triancinolona Acetonida/administração & dosagem , Triancinolona Acetonida/uso terapêutico , Feminino , Ranibizumab/administração & dosagem , Ranibizumab/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Tomografia de Coerência Óptica/métodos , Pessoa de Meia-Idade , Angiofluoresceinografia/métodos , Glucocorticoides/uso terapêutico , Glucocorticoides/administração & dosagem , Idoso , Vasos Retinianos/patologia , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/efeitos dos fármacos , Quimioterapia CombinadaRESUMO
Loss of the inner blood-retinal barrier (BRB) integrity is a main feature of ocular diseases such as diabetic macular edema. However, there is a lack of clarity on how inner BRB function is modulated within the diabetic retina. The current study examined whether eucalyptol inhibited inner BRB destruction and aberrant retinal angiogenesis in 33 mM glucose-exposed human retinal microvascular endothelial (RVE) cells and db/db mice. This study further examined the molecular mechanisms underlying endothelial dysfunction including retinal endoplasmic reticulum (ER) stress and angiopoietin (Ang)/Tie axis in conjunction with vascular endothelial growth factor (VEGF). Eucalyptol is a naturally occurring monoterpenoid and an achiral aromatic component of many plants including eucalyptus leaves. Nontoxic eucalyptol reduced the production of amyloid-ß (Aß) protein in glucose-loaded RVE cells and in diabetic mice. This natural compound blocked apoptosis of Aß-exposed RVE cells in diabetic mouse eyes by targeting ER stress via the inhibition of PERK-eIF2α-ATF4-CHOP signaling. Eucalyptol promoted activation of the Ang-1/Tie-2 pathway and dual inhibition of Ang-2/VEGF in Aß-exposed RVE cells and in diabetic eyes. Supply of eucalyptol reversed the induction of junction proteins in glucose/Aß-exposed RVE cells within the retina and reduced permeability. In addition, oral administration of eucalyptol reduced vascular leaks in diabetic retinal vessels. Taken together, these findings clearly show that eucalyptol inhibits glucose-induced Aß-mediated ER stress and manipulates Ang signaling in diabetic retinal vessels, which ultimately blocks abnormal angiogenesis and loss of inner BRB integrity. Therefore, eucalyptol provides new treatment strategies for diabetes-associated RVE defects through modulating diverse therapeutic targets including ER stress, Ang-1/Tie-2 signaling, and Ang-2/VEGF.
Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Estresse do Retículo Endoplasmático , Eucaliptol , Transdução de Sinais , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Eucaliptol/farmacologia , Camundongos , Retinopatia Diabética/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/patologia , Transdução de Sinais/efeitos dos fármacos , Humanos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Barreira Hematorretiniana/metabolismo , Barreira Hematorretiniana/efeitos dos fármacos , Masculino , Apoptose/efeitos dos fármacos , Angiopoietina-1/metabolismo , Camundongos Endogâmicos C57BL , Vasos Retinianos/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/patologiaRESUMO
PURPOSE: To investigate the effects of topically applied 1% tropicamide, 2.5% phenylephrine and 1% cyclopentolate on retinal vessel calliper (VC) using optical coherence tomography (OCT). METHODS: Patients who came to the ophthalmology clinic for routine examination and whose OCT films were taken before dilatation and after 30 min of last dilatation drop were included in the study. 90 ophthalmologically healthy subjects were divided into 3 groups of 30 subject each according to the application of the drops as follows: Tropicamide group (Group 1), Phenylephrine group (Group 2), Cyclopentolate group (Group 3). The right eyes of the subjects were dilated with drops and the left eyes were taken as the control group. VC of retinal artery and vein passing through an area one-half to one-disc diameter from the optic disc margin were measured from OCT films. The mean of the sum of superior retinal artery (SRA) and inferior retinal artery (IRA) VC and the mean of the sum of superior retinal vein (SRV) and inferior retinal vein (IRV) VC before and after the drop were compared. RESULTS: There was no statistically significant change in the mean sum of SRA and IRA VC and the mean sum of SRV and IRV VC before and after dilatation drops in all three groups. CONCLUSION: Dilatation drops have no statistically significant effect on retinal artery and vein VC.
Assuntos
Ciclopentolato , Midriáticos , Soluções Oftálmicas , Fenilefrina , Vasos Retinianos , Tomografia de Coerência Óptica , Tropicamida , Humanos , Midriáticos/administração & dosagem , Soluções Oftálmicas/administração & dosagem , Tropicamida/administração & dosagem , Masculino , Feminino , Adulto , Ciclopentolato/administração & dosagem , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/diagnóstico por imagem , Fenilefrina/administração & dosagem , Adulto Jovem , Pessoa de Meia-IdadeRESUMO
PURPOSE: To study the effect of brimonidine on vascular density and flow index of optic nerve head (ONH) and macula in primary open angle glaucoma (POAG) using optical coherence tomography angiography (OCTA). METHODS: Twenty-three brimonidine-naïve POAG patients were started on brimonidine. They underwent OCTA ONH and macula before commencing brimonidine and one month thereafter. Systemic arterial blood pressure (SABP) and intraocular pressure (IOP) were measured at each visit to calculate mean ocular perfusion pressure (MOPP). The OCT angiograms were analyzed using ImageJ software to calculate ONH and macular flow indices. RESULTS: Thirty-seven eyes (23 patients) with a mean age of 56.7 ± 12.49 years were included of whom 60.8% were males. Brimonidine was associated with an increase in the superficial flow index (SFI) (P-value = 0.02) and optic nerve head flow index (ONHFI) (P-value = 0.01). Also, superficial vascular density (SVD) for whole image, superior-hemi and fovea increased (P-value = 0.03, 0.02, 0.03 respectively). ONH inferior-hemi vascular density decreased (P-value = 0.01) despite an increase in inferior quadrant retinal nerve fiber layer thickness (RNFLT) (P-value = 0.03). There was no statistically significant correlation between flow indices and MOPP at baseline and follow-up. A moderate negative correlation was found between SVD and DVD at the fovea and MOPP at baseline and follow-up (P-value = 0.03, 0.05) (P-value = 0.02, 0.01) respectively. CONCLUSIONS: Brimonidine was associated with an increase in SFI, ONHFI and SVD indicating improved GCC and RNFL perfusion in POAG. Despite the increase in inferior quadrant RNFLT, the concomitant decrease in inferior-hemi ONHVD precluded a conclusion of hemodynamically-mediated improvement of RNFLT.
Assuntos
Tartarato de Brimonidina , Angiofluoresceinografia , Glaucoma de Ângulo Aberto , Pressão Intraocular , Macula Lutea , Disco Óptico , Vasos Retinianos , Tomografia de Coerência Óptica , Humanos , Glaucoma de Ângulo Aberto/fisiopatologia , Glaucoma de Ângulo Aberto/tratamento farmacológico , Glaucoma de Ângulo Aberto/diagnóstico , Masculino , Disco Óptico/irrigação sanguínea , Tartarato de Brimonidina/administração & dosagem , Tartarato de Brimonidina/farmacologia , Tartarato de Brimonidina/uso terapêutico , Pessoa de Meia-Idade , Feminino , Tomografia de Coerência Óptica/métodos , Macula Lutea/irrigação sanguínea , Macula Lutea/diagnóstico por imagem , Pressão Intraocular/fisiologia , Pressão Intraocular/efeitos dos fármacos , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/fisiopatologia , Vasos Retinianos/efeitos dos fármacos , Angiofluoresceinografia/métodos , Fluxo Sanguíneo Regional/fisiologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Idoso , Fundo de Olho , Estudos Prospectivos , Campos Visuais/fisiologia , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Anti-Hipertensivos/uso terapêutico , Fibras Nervosas/patologia , Fibras Nervosas/efeitos dos fármacos , Adulto , SeguimentosRESUMO
BACKGROUND: Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H2) is widely considered as a useful neuroprotective and antioxidative therapeutic method for hypoxic-ischemic disease without toxic effects. However, whether H2 provides physiological angiogenesis promotion, neovascularization suppression and glial protection in the progression of ROP is largely unknown.This study aims to investigate the effects of H2 on retinal angiogenesis, neovascularization and neuroglial dysfunction in the retinas of oxygen-induced retinopathy (OIR) mice. METHODS: In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H2) inhalation were administered. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. To count the number of neovascularization endothelial nuclei, routine HE staining of retinal sections was conducted. Immunohistochemistry was performed using DyLight 594 labeled GSL I-isolectin B4 (IB4), as well as primary antibodies against proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), and Iba-1. Western blots were used to measure the expression of NF-E2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), Notch1, Dll4, and HIF-1α. Additionally, the expression of target genes such as NQO1, HO-1, Notch1, Hey1, Hey2, and Dll4 was measured. Human umbilical vein endothelial cells (HUVECs) treated with H2 under hypoxia were used as an in vitro model. RT-PCR was used to evaluate the mRNA expression of Nrf2, Notch/Dll4, and the target genes. The expression of reactive oxygen species (ROS) was observed using immunofluorescence staining. RESULTS: Our results indicate that 3-4% H2 does not disturb retinal physiological angiogenesis, but ameliorates vaso-obliteration and neovascularization in OIR mice. Moreover, H2 prevents the decreased density and reverses the morphologic and functional changes in retinal astrocytes caused by oxygen-induced injury. In addition, H2 inhalation reduces microglial activation, especially in the area of neovascularization in OIR mice. H2 plays a protective role in vascular regeneration by promoting Nrf2 activation and suppressing the Dll4-induced Notch signaling pathway in vivo. Also, H2 promotes the proliferation of HUVECs under hypoxia by negatively regulating the Dll4/Notch pathway and reducing ROS levels through Nrf2 pathway aligning with our findings in vivo.Moreover, the retinal oxygen-sensing mechanisms (HIF-1α/VEGF) are also involved in hydrogen-mediated retinal revascularization and neovascularization suppression. CONCLUSIONS: Collectively, our results indicate that H2 could be a promising therapeutic agent for POR treatment and that its beneficial effect in human ROP might involve the activation of the Nrf2-Notch axis as well as HIF-1α/VEGF pathways.
Assuntos
Modelos Animais de Doenças , Hidrogênio , Neuroglia , Oxigênio , Neovascularização Retiniana , Retinopatia da Prematuridade , Animais , Hidrogênio/farmacologia , Neovascularização Retiniana/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Camundongos , Retinopatia da Prematuridade/tratamento farmacológico , Camundongos Endogâmicos C57BL , Retina/efeitos dos fármacos , Animais Recém-Nascidos , Regeneração/efeitos dos fármacos , Imuno-Histoquímica , Vasos Retinianos/efeitos dos fármacosRESUMO
Purpose: To compare changes in superficial retinal vascular density (SRVD), deep retinal vascular density (DRVD), and retinal thickness (RT) of the macular zone after repeated low-level red light (RLRL) and 0.01% atropine exposure in premyopic schoolchildren. Methods: Prospective randomized trial. Sixty-nine schoolchildren with cycloplegic refraction >-0.75 D and ≤0.50 D were randomly assigned to RLRL and 0.01% atropine groups. SRVD, DRVD, and RT were measured using swept-source optical coherence tomography at baseline and six months. The macular zone was divided into three concentric rings (fovea, parafovea, and perifovea) using the Early Treatment Diabetic Retinopathy Study. Results: After six months, the whole, parafoveal, and perifoveal SRVD significantly increased in the two groups (all P < 0.05). Multivariate regression analyses showed that none of these changes varied significantly between the two groups (all P > 0.05), whereas foveal SRVD remained stable in both groups (all P > 0.05). In the RLRL group, the whole and perifoveal DRVD increased significantly (all P < 0.05), whereas no statistical difference was observed in the foveal and parafoveal DRVD. DRVD remained stable in the 0.01% atropine group (all P > 0.05). No significant differences were observed in RT changes between the two groups (all P > 0.05). In comparison, there were no significant changes in SRVD, DRVD, or RT after six months in the placebo group in our previous study. Conclusions: SRVD increased similarly in the RLRL and 0.01% atropine groups, whereas DRVD increased only in the former group. There were no significant RT changes in either group after six months of treatment in premyopic schoolchildren. Translational Relevance: This research observed the effects of low-level red light and 0.01% atropine on retinal vasculature, offering valuable insights into myopia progression prevention.
Assuntos
Atropina , Midriáticos , Vasos Retinianos , Tomografia de Coerência Óptica , Humanos , Atropina/administração & dosagem , Atropina/farmacologia , Masculino , Feminino , Criança , Estudos Prospectivos , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/diagnóstico por imagem , Midriáticos/administração & dosagem , Midriáticos/farmacologia , Miopia/tratamento farmacológico , Miopia/patologia , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/uso terapêutico , Fototerapia/métodos , Densidade Microvascular/efeitos dos fármacos , Luz VermelhaRESUMO
To investigate the effects and molecular mechanisms of wedelolactone (WEL) on high glucose-induced injury of human retinal vascular endothelial cells (HRECs). The cell injury model was established by incubating HRECs with 30 mmol/L glucose for 24 hour. HRECs were divided into control (Con) group, high glucose (HG) group, HGâ +â WEL-low dose (L) group, HGâ +â WEL-medium dose (M), HGâ +â WEL-high dose (H) group, HGâ +â miR-NC group, HGâ +â miR-190 group, HGâ +â WELâ +â antimiR-NC group, HGâ +â WELâ +â antimiR-190 group. The kit detects cellular reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) content; cell apoptosis was analyzed by flow cytometry; miR-190 expression was detected by real-time quantitative PCR (RT-qPCR). Compared with Con group, the levels of ROS and MDA in the HG group were significantly increased (Pâ <â .01), the SOD activity and the expression of miR-190 expression were significantly decreased (Pâ <â .05), and the apoptosis rate was significantly increased (Pâ <â .01). Compared with HG group, the levels of ROS and MDA in HGâ +â WEL-L group, HGâ +â WEL-M group and HGâ +â WEL-H group were significantly decreased (Pâ <â .05), SOD activity and miR-190 expression were significantly increased (Pâ <â .05), and apoptosis rate was significantly reduced (Pâ <â .05). Compared with the HGâ +â miR-NC group, the levels of ROS and MDA in HGâ +â miR-190 group were significantly reduced (Pâ <â .01), SOD activity was significantly increased (Pâ <â .01), and apoptosis rate was significantly reduced (Pâ <â .05). Compared with the HGâ +â WELâ +â antimiR-NC group, the ROS level and MDA content in the HGâ +â WELâ +â antimiR-190 group were significantly increased (Pâ <â .05), SOD activity was significantly decreased (Pâ <â .05), and apoptosis rate was significantly increased (Pâ <â .05). Wedelolactone can attenuate high glucose-induced HRECs apoptosis and oxidative stress by up-regulating miR-190 expression.
Assuntos
Apoptose , Cumarínicos , Células Endoteliais , MicroRNAs , Espécies Reativas de Oxigênio , Humanos , Apoptose/efeitos dos fármacos , Células Cultivadas , Cumarínicos/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Glucose/efeitos adversos , Malondialdeído/metabolismo , MicroRNAs/efeitos dos fármacos , MicroRNAs/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Superóxido Dismutase/metabolismoAssuntos
COVID-19 , Glucocorticoides , Microcirculação , Vasos Retinianos , Humanos , Microcirculação/efeitos dos fármacos , COVID-19/complicações , Glucocorticoides/uso terapêutico , Glucocorticoides/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Vasos Retinianos/patologia , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/efeitos dos fármacos , SARS-CoV-2 , Idoso , Tratamento Farmacológico da COVID-19 , Retina/patologiaRESUMO
PURPOSE: To evaluate changes in retinal microvascular density and choroidal vascularity in patients with retinoblastoma (RB) after intra-arterial chemotherapy (IAC). DESIGN: Retrospective clinical cohort study. METHODS: This study included 12 unilateral RB eyes treated with IAC (RB tumor), 12 contralateral normal eyes (RB fellow), and 12 healthy controls. The macular retinal thickness and retinal microvascular structure, including the foveal avascular zone (FAZ) area, macular and peripapillary superficial vessel density (SVD), and deep vessel density (DVD), were measured by optical coherence tomography angiography (OCTA). The choroidal thickness (ChT) and choroidal vascularity, including total choroidal area (TCA), luminal area (LA), stromal area (SA), and choroidal vascularity index (CVI), were measured by spectral-domain optical coherence tomography (SD-OCT). A comparison among the 3 groups was conducted, and the correlations among the parameters were analyzed. RESULTS: Among the 3 cohorts, the foveal retinal thickness, SVD, DVD, ChT, TCA, LA, SA, and CVI were significantly lower in RB tumor compared to RB fellow and the control eyes (all P < .01). There were no significant differences in the parameters between the contralateral and control eyes. The correlation analyses indicated a significant negative correlation between the total melphalan dose and foveal and parafoveal DVD, ChT, and LA. CONCLUSIONS: The retinal microvascular density and choroidal vascularity were lower in unilateral RB treated with IAC, and seemed to be related to the total melphalan dose. There were no measurable changes in the contralateral eyes.
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Corioide , Angiofluoresceinografia , Infusões Intra-Arteriais , Melfalan , Microvasos , Neoplasias da Retina , Vasos Retinianos , Retinoblastoma , Tomografia de Coerência Óptica , Humanos , Retinoblastoma/tratamento farmacológico , Neoplasias da Retina/tratamento farmacológico , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Corioide/irrigação sanguínea , Masculino , Feminino , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/efeitos dos fármacos , Angiofluoresceinografia/métodos , Pré-Escolar , Melfalan/administração & dosagem , Microvasos/efeitos dos fármacos , Lactente , Criança , Antineoplásicos Alquilantes/administração & dosagem , Densidade Microvascular , Acuidade Visual/fisiologiaRESUMO
The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we used streptozotocin-induced diabetic mice to investigate the early pathogenic alterations in DR and the protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors against these alterations. Retinal vascular leakage was assessed by dextran fluorescence angiography. Retinal thickness and vascular leakage were increased 2 and 4 weeks after onset of diabetes, respectively. Immunostaining showed that morphological change of microglia (amoeboid form) was observed at 2 weeks. Subsequently, increased angiopoietin-2 expression, simultaneous loss of pericytes and endothelial cells, decreased vessel density, retinal hypoxia, and increased vascular endothelial growth factor (VEGF)-A/VEGF receptor system occurred at 4 weeks. SGLT2 inhibitors (luseogliflozin and ipragliflozin) had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. Furthermore, both inhibitors at this dose attenuated microglia morphological changes and these early pathogenic alterations in DR. In vitro study showed both inhibitors attenuated the lipopolysaccharide-induced activation of primary microglia, along with morphological changes toward an inactive form, suggesting the direct inhibitory effect of SGLT2 inhibitors on microglia. In summary, SGLT2 inhibitors may directly prevent early pathogenic mechanisms, thereby potentially playing a role in preventing DR.
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Diabetes Mellitus Experimental , Retinopatia Diabética , Microglia , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Retinopatia Diabética/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Masculino , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Retina/patologia , Retina/efeitos dos fármacos , Retina/metabolismo , Camundongos Endogâmicos C57BL , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/patologia , Vasos Retinianos/metabolismo , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Angiopoietina-2/metabolismo , Angiopoietina-2/antagonistas & inibidoresRESUMO
Introducción y objetivos Investigar el efecto de la acetazolamida (AZ) sobre la microvasculatura ocular retiniana y coroidea en la mácula y los capilares peripapilares radiales (CPR) del disco óptico con angiografía-OCT (OCTA). Materiales y métodos Estudio transversal observacional de 9meses de duración. Se reclutaron 45 ojos de 45 participantes sanos que se sometieron a cirugía de cataratas. Se comparó la densidad de vasos (DV) de la retina macular y la coriocapilar (CC) y la DV de la CPR en la zona del disco óptico antes y 60 min después de administrar 250mg de AZ por vía oral. También se midieron la presión intraocular (PIO) y la presión arterial (PA) sistémica antes de cada exploración. Resultado La edad media era de 73,1±6,9 años. La densidad de vasos (DV) en el plexo capilar superficial (PCS) y profundo (PCP) de la retina y la CC en el área macular no mostraron cambios significativos (p>0,5, para todos los parámetros). La DV en los CPR no mostró cambios significativos con la AZ (p>0,5, para todos los parámetros). El grosor foveal y parafoveal aumentó de 248,98 (± 23,89) a 250,33 (± 23,74) y de 311,62 (± 16,53) a 311,98 (± 16,38) (p<0,001 y p=0,046), respectivamente. La PIO disminuyó de 13,2 (± 3,0) mmHg a 11,8 (± 3,2) mmHg (p<0,001), mientras que la PA sistólica y diastólica disminuyó de 144,8 (± 21,8) a 137,7 (± 19,0) y de 80,0 (± 12,7) a 76,2 (± 11,7) (p=0,021 y p=0,030), respectivamente. Conclusiones Las imágenes de OCTA no revelaron cambios significativos en la VD del disco óptico ni en el VD de la retina y la coroides en la mácula con AZ oral una hora después de su administración en participantes por lo demás sanos que se sometieron a cirugía de cataratas (AU)
Introduction and objectives To investigate the effect of acetazolamide (AZ) on the retinal and choroidal ocular microvasculature in the macula and radial peripapillary capillaries (RPC) of the optic disc with OCT Angiography (OCTA). Materials and method Nine-month observational cross-sectional study. Forty-five eyes from 45 healthy participants who underwent cataract surgery were recruited. Macular retina and choriocapillaris vessel density (VD) and RPC VD in the optic disc area were compared before and 60minutes after 250mg acetazolamide per os. Intraocular pressure (IOP) and systemic blood pressure (BP) were also measured before each scan. Result Mean age was 73.1±6.9 years. VDs in the superficial (SCP) and deep (DCP) capillary plexus of the retina and the choriocapillaris (CC) in the macular area showed no significant change (p>0.5, for all parameters). VD in the RPC showed no significant change with AZ (p>0.5, for all parameters). Foveal and parafoveal thickness increased from 248.98 (±23.89) to 250.33 (±23.74) and from 311.62 (±16.53) to 311.98 (±16.38) (p<0.001 and p=0.046), respectively. IOP decreased from 13.2 (±3.0) mmHg to 11.8 (±3.2) mmHg (p<0.001), while systolic and diastolic BP decreased from 144.8 (±21.8) to 137.7 (±19.0) and from 80.0 (±12.7) to 76.2 (±11.7) (p=0.021 and p=0.030), respectively. Conclusion OCTA imaging did not reveal any significant changes in the VD of the optic disc or the retinal and choroidal VD in the macula with oral AZ one hour after its administration in otherwise healthy participants who underwent cataract surgery (AU)
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Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Acetazolamida/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Vasos Retinianos/efeitos dos fármacos , Disco Óptico/efeitos dos fármacos , Corioide/efeitos dos fármacos , Estudos Transversais , Tomografia de Coerência Óptica , Angiografia por Tomografia Computadorizada , Vasos Retinianos/diagnóstico por imagem , Disco Óptico/diagnóstico por imagem , Corioide/diagnóstico por imagemRESUMO
The Notch signaling pathway is an important therapeutic target for the treatment of inflammatory diseases and cancer. We previously created ligand-specific inhibitors of Notch signaling comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain, called Notch decoys, which bound ligands, blocked Notch signaling, and showed anti-tumor activity with low toxicity. However, the study of their function depended on virally mediated expression, which precluded dosage control and limited clinical applicability. We have refined the decoy design to create peptibody-based Notch inhibitors comprising the core binding domains, EGF-like repeats 10-14, of either Notch1 or Notch4. These Notch peptibodies showed high secretion properties and production yields that were improved by nearly 100-fold compared to previous Notch decoys. Using surface plasmon resonance spectroscopy coupled with co-immunoprecipitation assays, we observed that Notch1 and Notch4 peptibodies demonstrate strong but distinct binding properties to Notch ligands DLL4 and JAG1. Both Notch1 and Notch4 peptibodies interfere with Notch signaling in endothelial cells and reduce expression of canonical Notch targets after treatment. While prior DLL4 inhibitors cause hyper-sprouting, the Notch1 peptibody reduced angiogenesis in a 3-dimensional in vitro sprouting assay. Administration of Notch1 peptibodies to neonate mice resulted in reduced radial outgrowth of retinal vasculature, confirming anti-angiogenic properties. We conclude that purified Notch peptibodies comprising EGF-like repeats 10-14 bind to both DLL4 and JAG1 ligands and exhibit anti-angiogenic properties. Based on their secretion profile, unique Notch inhibitory activities, and anti-angiogenic properties, Notch peptibodies present new opportunities for therapeutic Notch inhibition.
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Inibidores da Angiogênese , Células Endoteliais , Receptor Notch1 , Receptor Notch4 , Animais , Camundongos , Inibidores da Angiogênese/genética , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Imunoprecipitação , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptor Notch4/genética , Receptor Notch4/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Vasos Retinianos/efeitos dos fármacos , Ressonância de Plasmônio de SuperfícieRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Lycium barbarum L., a classical traditional Chinese Medicine, has long been used to treat ocular diseases. Lycium barbarum polysaccharides (LBP) is an effective component of Lycium barbarum L. with a wide range of pharmacological activities. This research aims to investigate the inhibition of high glucose-induced angiogenesis by LBP in RF/6A cells. MATERIALS AND METHODS: A high-glucose-induced angiogenesis model was established using monkey retinal vascular endothelial (RF/6A) cells. Different dosages administration times of LBP and glucose concentrations were tested. Under the optimized conditions, RF/6A cells were treated with LBP for 48 h, followed by another 48-h culture in high glucose (25 mmol/L) medium. The effect and mechanism of LBP were investigated following the treatment. RESULTS: The expression of miR-15a-5p and miR-15a-3p in RF/6A cells decreased significantly after 48 h of 25 or 50 mmol/L high glucose treatment. The expression of miR-15a-5p was higher than that of miR-15a-3p. Mimic-miR-15a-5p or 600 mg/L LBP could increase the apoptosis of cells and the total length of vascular branches. The expression of VEGFA, VEGFR2, and ANG2 proteins was reduced, while the expression of ANG1 protein was elevated. Expression of ASM mRNA and protein was also inhibited. CONCLUSIONS: LBP attenuates diabetic retinal angiogenesis by rescuing the expression of miR-15a-5p in RF/6A cells.
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Retinopatia Diabética/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , MicroRNAs/genética , Neovascularização Patológica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Retinopatia Diabética/genética , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Haplorrinos , Neovascularização Patológica/genética , Vasos Retinianos/citologia , Vasos Retinianos/efeitos dos fármacosRESUMO
BACKGROUND: Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat. OBJECTIVES: We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort. METHODS: In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC-tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light-induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors. RESULTS: Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light-induced venular dilation (ß percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (ß: -0.04 SD; 95% CI: -0.08, -0.00 SD), the effect sizes were small and their biological relevance can be questioned. CONCLUSIONS: We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions.
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Diabetes Mellitus/fisiopatologia , Dieta/efeitos adversos , Produtos Finais de Glicação Avançada/administração & dosagem , Microcirculação/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição/efeitos dos fármacos , Idoso , Biomarcadores/sangue , Cromatografia Líquida , Estudos Transversais , Feminino , Humanos , Rim/irrigação sanguínea , Lisina/administração & dosagem , Lisina/análogos & derivados , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Ornitina/administração & dosagem , Estudos Prospectivos , Vasos Retinianos/efeitos dos fármacos , Pele/irrigação sanguíneaRESUMO
Diabetic retinopathy (DR) is a serious complication of diabetes mellitus. The purpose of this study was to investigate the potential functional role of long non-coding RNA TUG1 in high glucose (HG)-stimulated human retinal microvascular endothelial cells (hRMECs). The results demonstrated that following 72 h of HG stimulation, enhanced proliferation, migration, and tube formation process were observed in hRMECs. Moreover, HG treatment markedly increased TUG1 expression in hRMECs, and knockdown of TUG1 notably restrained the aberrant phenotypes of hRMECs induced by HG. Mechanistically, TUG1 may serve as a competing endogenous RNA (ceRNA) for miR-145, thereby blocking the repression on VEGF-A in hRMECs. Rescue experiments further indicated that inhibition of miR-145 abolished the beneficial role of TUG1 knockdown in HG-treated hRMECs. Our data suggested that knockdown of TUG1 protects hRMECs against HG stimulation partly by regulating miR-145/VEGF-A axis.