MicroRNA-126 inhibits ischemia-induced retinal neovascularization via regulating angiogenic growth factors

Bai, Yanyan; Bai, Xia; Wang, Zhaoyue; Zhang, Xiaofeng; Ruan, Changgeng; Jiang, Miao

doi:10.1016/j.yexmp.2011.04.016

Cited by 98 publications

(89 citation statements)

References 34 publications

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“…Although recent studies reported the expression profiles of many miRNAs in the normal retinas of mice, including miR-329, its targets and function were unknown (44,45). Moreover, only a few miRNAs have been identified to regulate OIR (46,47). Here, we provide the first evidence that endogenous miR-329 is decreased in OIR retinas compared with those of healthy eyes.…”

Section: Discussionmentioning

confidence: 63%

MicroRNA 329 Suppresses Angiogenesis by Targeting CD146

Wang

Luo

Duan

et al. 2013

Molecular and Cellular Biology

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b CD146, an endothelial biomarker, has been shown to be aberrantly upregulated during pathological angiogenesis and functions as a coreceptor for vascular endothelial growth factor receptor 2 (VEGFR-2) to promote disease progression. However, the regulatory mechanisms of CD146 expression during angiogenesis remain unclear. Using a microRNA screening approach, we identified a novel negative regulator of angiogenesis, microRNA 329 (miR-329), that directly targeted CD146 and inhibited CD146-mediated angiogenesis in vitro and in vivo. Endogenous miR-329 expression was downregulated by VEGF and tumor necrosis factor alpha (TNF-␣), resulting in the elevation of CD146 in endothelial cells. Upregulation of CD146 facilitated an endothelial response to VEGF-induced SRC kinase family (SKF)/p38 mitogen-activated protein kinase (MAPK)/NF-B activation and consequently promoted endothelial cell migration and tube formation. Our animal experiments showed that treatment with miR-329 repressed excessive CD146 expression on blood vessels and significantly attenuated neovascularization in a mouse model of pathological angiogenesis. Our findings provide the first evidence that CD146 expression in angiogenesis is regulated by miR-329 and suggest that miR-329 could present a potential therapeutic tool for the treatment of angiogenic diseases.

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Section: Discussionmentioning

confidence: 63%

MicroRNA 329 Suppresses Angiogenesis by Targeting CD146

Wang

Luo

Duan

et al. 2013

Molecular and Cellular Biology

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“…Although miR-126 is required for VEGF signaling in ECs, its overexpression could repress VEGF expression in other cell types, highlighting the cell type-specific function of this miRNA. [15][16][17]20,23,26 We hypothesized that the differential effect of miR-126 strands overexpression/knockdown in different cell types could be explained by differential expression of VEGF and signaling pathways in different cells. We have shown that miRNA mimic is distributed in both choroidal vasculature and its neighboring RPE cells after subretinal delivery (Figure 4a).…”

Section: Repression Of Vegf Expression By Mir-126-3p In Rpe Cellsmentioning

confidence: 99%

“…These results are consistent with recent reports, suggesting that VEGFA is a miR-126-3p target. 23, 26 We also investigated additional mechanism that accounts for specific miR-126-3p function in RPE cells. RPE expression of αB-Crystallin (CryaB), a small heat shock protein, has been associated with drusen deposit during AMD progression.…”

Section: Mir-126-3p Regulates Vegf In Rpes Cells By Two Distinct Mechmentioning

confidence: 99%

Strand and Cell Type-specific Function of microRNA-126 in Angiogenesis

et al. 2016

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microRNAs or miRs have been shown to be pivotal modulators of vascular development. The strand and cell typespecific function of miR-126 in angiogenesis, especially pathological angiogenesis, remains poorly defined. We characterized the retinal vascular phenotype of miR-126 −/− mice, and tested the function of miR-126 strands (miR-126-3p and -5p) using in vitro angiogenesis models and a mouse model of neovascular age-related macular degeneration. We found that miR-126 is critical for retinal vascular development but has dual function in pathological angiogenesis. miR-126 −/− mice showed defective postnatal retinal vascular development and remodeling, which is partially rescued by genetic knockout of its target gene Spred-1. Surprisingly, either silencing miR-126-3p by LNA-antimiR or overexpressing miR-126-3p by miRNA mimic repressed laser-induced choroidal neovascularization. To dissect the underlying mechanism, we found in endothelial cells, silencing of miR-126-3p repressed angiogenesis, while overexpression of miR-126-5p enhanced angiogenesis. However, in retinal pigment epithelial cells, miR-126-3p repressed vascular endothelial growth factor (VEGF-A) expression via a novel mechanism of regulating αB-Crystallin promoter activity and by directly targeting VEGF-A 3′-untranslated region. These findings provide first genetic evidence that miR-126 is required for the development of different retinal vascular layers, and also uncover a strand and cell type-specific function of miR-126 in ocular pathological angiogenesis. Received 17 March 2016; accepted 11 May 2016; advance online publication 21 June 2016 advance online publication 21 June . doi:10.1038 advance online publication 21 June /mt.2016 INTRODUCTIONThe retina has been an excellent model to study developmental and pathological angiogenesis. Vascularization of the mouse outer retina occurs through two waves of angiogenesis after birth, when endothelial cells (ECs) sprout from the central retinal artery to the peripheral region and then to the intermediate and deep layers of the retinal vascular plexus.1,2 Pathological angiogenesis in the eye is the most common cause of blindness at all ages and underlies conditions such as retinopathy of prematurity in children, diabetic retinopathy in young adults and age-related macular degeneration (AMD) in the elderly. AMD is a degenerative disease of the retina and the leading cause of blindness among the elderly.3 Neovascular (or wet) AMD, which accounts for the majority of acute vision loss in AMD, is characterized by choroidal neovascularization (CNV), a process involving abnormal growth of blood vessels from the choroid into the retina. Vascular endothelial growth factor (VEGF), which is highly expressed in the retinal pigment epithelial (RPE) cells in the eye, is a major cytokine driving neovascularization and vascular permeability during CNV. Several FDA-approved anti-VEGF agents, including Macugen, Lucentis and Eylea, are the current mainstay for wet AMD treatment. 4-6Although anti-VEGF agents have marked...

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“…Several miRs, including let-7, miR-375, miR-9, miR-103/107, miR-143/145, and miR-144, have been shown to regulate insulin production, release, or insulin sensitivity (16)(17)(18)(19)(20)(21)(22). A number of miRs have been shown to be significantly regulated in the retinas or retinal ECs (RECs) in streptozotocin-induced or Akita (type I diabetic) DR animal models or in the oxygen-induced retinopathy model (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Particularly, miR-146a and miR-146b are upregulated in the RECs of diabetic rats and act as negative feedback on NF-B activation to control the inflammatory response (23,33); miR-200b and miR-126 are downregulated in a DR mouse model and regulate VEGF expression during retinal neovascularization (25,29); miR-200b downregulation was also found in the retinas of patients with diabetes (25,34).…”

mentioning

confidence: 99%

“…A number of miRs have been shown to be significantly regulated in the retinas or retinal ECs (RECs) in streptozotocin-induced or Akita (type I diabetic) DR animal models or in the oxygen-induced retinopathy model (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Particularly, miR-146a and miR-146b are upregulated in the RECs of diabetic rats and act as negative feedback on NF-B activation to control the inflammatory response (23,33); miR-200b and miR-126 are downregulated in a DR mouse model and regulate VEGF expression during retinal neovascularization (25,29); miR-200b downregulation was also found in the retinas of patients with diabetes (25,34). However, miR-200b was also shown to be significantly upregulated in the retinas of Akita rats and could contribute to increased cell death in DR (26).…”

mentioning

confidence: 99%

let-7 Contributes to Diabetic Retinopathy but Represses Pathological Ocular Angiogenesis

Zhou

Frost

Anderson

et al. 2017

Molecular and Cellular Biology

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The in vivo function of microRNAs (miRs) in diabetic retinopathy (DR) and age-related macular degeneration (AMD) remains unclear. We report here that let-7 family members are expressed in retinal and choroidal endothelial cells (ECs). In ECs, overexpression of let-7 by adenovirus represses EC proliferation, migration, and networking in vitro, whereas inhibition of the let-7 family with a locked nucleic acid (LNA)-anti-miR has the opposite effect. Mechanistically, silencing of the let-7 target HMGA2 gene mimics the phenotype of let-7 overexpression in ECs. let-7 transgenic (let-7-Tg) mice show features of nonproliferative DR, including tortuous retinal vessels and defective pericyte coverage. However, these mice develop significantly less choroidal neovascularization (CNV) compared to wild-type controls after laser injury. Consistently, silencing of let-7 in the eye increased laser-induced CNV in wild-type mice. Together, our data establish a causative role of let-7 in nonproliferative diabetic retinopathy and a repressive function of let-7 in pathological angiogenesis, suggesting distinct implications of let-7 in the pathogenesis of DR and AMD.KEYWORDS let-7, endothelial cells, angiogenesis, diabetic retinopathy, choroidal, neovascularization, AMD T he retina has been an excellent model for studying the mechanism of angiogenesis. Retinal vascularization in mice begins after birth, when endothelial cells (ECs) sprout from the central retinal artery to the peripheral region and then to the intermediate and deep retinal layers (1, 2). Pathological angiogenesis in the eye is the most common cause of blindness at all ages and underlies conditions such as retinopathy of prematurity in children, diabetic retinopathy (DR) in young adults, and age-related macular degeneration (AMD) in the elderly. DR is the leading cause of blindness in working-age adults (18 to 64 years old), with a prevalence of 5.4% (ϳ7.7 million people) in the United States (3). Early-stage DR (or nonproliferative DR [NPDR]) is characterized by pericyte loss, basement membrane thickening, and EC dysfunction. Proliferative diabetic retinopathy (PDR) develops at the advanced stage and is associated with new blood vessel growth along the retina and the vitreous surface. AMD is a degenerative disease of the retina and the leading cause of blindness among the elderly (4). Neovascular (or wet) AMD, which accounts for the majority of acute vision loss in AMD, is characterized by choroidal neovascularization (CNV), a process involving abnormal growth of blood vessels from the choroid into the retina. Vascular endothelial growth factor (VEGF) is a major cytokine driving neovascularization and vascular permeability during CNV and diabetic edema. Several U.S. Food and Drug Administration-approved anti-VEGF agents are the current mainstay for wet AMD treatment and have been recently approved for

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MicroRNA-126 inhibits ischemia-induced retinal neovascularization via regulating angiogenic growth factors

Cited by 98 publications

References 34 publications

MicroRNA 329 Suppresses Angiogenesis by Targeting CD146

MicroRNA 329 Suppresses Angiogenesis by Targeting CD146

Strand and Cell Type-specific Function of microRNA-126 in Angiogenesis

let-7 Contributes to Diabetic Retinopathy but Represses Pathological Ocular Angiogenesis

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