MicroRNAs Regulate Ocular Neovascularization

Shen, Jing; Yang, Xinmin; Xie, Bing; Chen, Yangjian; Swaim, Mara; Hackett, Sean F.; Campochiaro, Peter A.

doi:10.1038/mt.2008.104

Cited by 195 publications

(166 citation statements)

References 46 publications

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“…Our findings of miR-150 suppression of vascular EC function is consistent with previous reports of miR-150 in regulating B-cell proliferation, development, and differentiation (22)(23)(24) and EC differentiation and vasculogenesis by targeting ZEB1 in human embryonic stem cells (25). A previous study identified multiple miRNAs substantially regulated in ischemic mouse retinas (26), yet the cell-specific roles of these miRNAs in the pathogenesis of neovascular eye diseases were not clear. In addition, several highly expressed miRNAs were identified in human ECs, including miR-126, miR-221/222, miR-21, the let-7 family, the miR-17∼92 cluster, and the miR-23∼24 cluster (27,28).…”

Section: Discussionsupporting

confidence: 82%

Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization

Liu

Sun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Pathologic ocular neovascularization commonly causes blindness. It is critical to identify the factors altered in pathologically proliferating versus normally quiescent vessels to develop effective targeted therapeutics. MicroRNAs regulate both physiological and pathological angiogenesis through modulating expression of gene targets at the posttranscriptional level. However, it is not completely understood if specific microRNAs are altered in pathologic ocular blood vessels, influencing vascular eye diseases. Here we investigated the potential role of a specific microRNA, miR-150, in regulating ocular neovascularization. We found that miR-150 was highly expressed in normal quiescent retinal blood vessels and significantly suppressed in pathologic neovessels in a mouse model of oxygen-induced proliferative retinopathy. MiR-150 substantially decreased endothelial cell function including cell proliferation, migration, and tubular formation and specifically suppressed the expression of multiple angiogenic regulators, CXCR4, DLL4, and FZD4, in endothelial cells. Intravitreal injection of miR-150 mimic significantly decreased pathologic retinal neovascularization in vivo in both wild-type and miR-150 knockout mice. Loss of miR-150 significantly promoted angiogenesis in aortic rings and choroidal explants ex vivo and laser-induced choroidal neovascularization in vivo. In conclusion, miR-150 is specifically enriched in quiescent normal vessels and functions as an endothelium-specific endogenous inhibitor of pathologic ocular neovascularization.neovascularization | endothelial cells | microRNA | miR-150 | retinopathy

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Section: Discussionsupporting

confidence: 82%

Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization

Liu

Sun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Kulshreshtha et al first reported that hypoxia was able to induce expression changes in miRNAs in cells in 2007 (16). Then, a number of studies revealed that the expression profiles of miRNAs also altered following ischemia and hypoxia in certain organs, including the retina, myocardium and hippocampus (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

miR-376b-5p regulates angiogenesis in cerebral ischemia

Huang

Zhang

et al. 2014

Molecular Medicine Reports

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Abstract. The profile of microRNAs (miRNAs) altered following middle cerebral artery occlusion (MCAO) and miRNAs are involved in angiogenesis following cerebral ischemia. miR-376b-5p was decreased following MCAO, however, whether miR-376b-5p is important in angiogenesis remains to be elucidated. The present study was designed to identify whether miR-376b-5p is involved in angiogenesis following cerebral ischemia and to elucidate the underlying mechanisms. A rat MCAO model was established and quantitative polymerase chain reaction was performed to analyze the mRNA expression level of miR-376b-5p for 1 to 7 days. In addition, the density of microvessels and the relative mRNA and protein levels of hypoxia-inducible factor-1 α (HIF-1α), vascular endothelial growth factor A (VEGFA) and Notch1 were measured. The miR-376b-5p mimic or the miR-376b-5p inhibitor were transfected into hypoxic human umbilical vein endothelial cells (HUVECs), and the proliferation, migration and tube formation were measured. To further examine the underlying mechanisms, shRNA was transfected into cells to knock down HIF-1α, and angiogenesis and the expression of associated molecules, including HIF-1α, VEGFA and Notch1 were compared between each group. Our results demonstrated that miR-376b-5p repressed angiogenesis in vivo and in vitro, and miR-376b-5p inhibited angiogenesis in HUVECs by targeting the HIF-1α-mediated VEGFA/Notch1 signaling pathway. These findings provide new insights into angiogenesis therapy for cerebral ischemia. IntroductionStroke is a life-threatening disease with a high incidence, high disability and high mortality rate, causing heavy economic burden to society and families. Cerebral infarction accounts for 80% of the total number of strokes (1). In the pathophysiological process of cerebral infarction, the recovery of the peripheral blood supply is an important factor for nerve cell prognosis (2). The clinical treatments for cerebral infarction, include thrombolysis, anticoagulation, blood pressure regulation and microcirculation improvement. The improvement and increase of blood supply in ischemic brain tissue, particularly in the ischemic penumbra, thereby improving energy metabolism of ischemic brain cells and saving neurons is one of the fundamental purposes and fundamental approaches for the treatment of cerebral ischemia.In recent years, a series of studies have revealed that good collateral circulation is able to reduce the infarct volume and reduce the risk of cerebral infarction recurrence (3,4). Clinical studies have provided preliminary evidence that promoting collateral circulation is able to lead to an improved clinical prognosis (5). Cerebral collateral circulation is blood flow which arrives in the ischemic area through other vessels (collateral or the newly formed vascular anastomosis) when arteries in the brain suffer severe stenosis or occlusion. Therefore, angiogenesis, as an effective method to improve the blood supply to the brain, is key for improving the prognosis of patients with stroke, and has...

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“…Shen et al (32) evaluated a later time point (3 d after high O 2 exposure on day 15 vs. 6 and 12 h on day 12 as studied here), when the events that lead to Hif1a and Vegfa up-regulation have already occurred. Shen et al (32) identified the levels of five miR-17 family members (miR-17-5p, miR-20a, miR-20b, miR-106a, and miR106b) increased at this later time point. We also tested the expression levels of all miR members from the miR-17 family at this same time point using a more sensitive and specific approach (quantitative RT-PCR).…”

Section: Low Levels Of Mir-17 Family In the Initial Steps Of The Angimentioning

confidence: 99%

“…In this case, finely tuned and complex biological processes, such as angiogenesis, require the concerted, simultaneous silencing of all miR-17 family members to bias the biological signals that ultimately lead to blood vessel formation. In a previous study, Shen et al (32) investigated miR alterations by microarray analysis using the ROP model. Shen et al (32) evaluated a later time point (3 d after high O 2 exposure on day 15 vs. 6 and 12 h on day 12 as studied here), when the events that lead to Hif1a and Vegfa up-regulation have already occurred.…”

Section: Low Levels Of Mir-17 Family In the Initial Steps Of The Angimentioning

confidence: 99%

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

Nunes

Dias-Neto

Cardó-Vila

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression profile of the miR-17 family in the murine retinopathy of prematurity (ROP) model, whereby Vegfa expression is highly enhanced at the early stage of retinal neovascularization, and we found simultaneous reduction of all miR-17 family members at this stage. Using gene reporter assays, we observed binding of these miRs to specific sites in the 3′ UTRs of Hif1a and Vegfa. Furthermore, overexpression of these miRs decreased HIF1A and VEGFA expression in vitro. Our data indicate that this miR-17 family elicits a regulatory synergistic down-regulation of Hif1a and Vegfa expression in this biological model. We propose the existence of a coordinated regulatory network, in which diverse miRs are synchronously regulated to target the Hif1a transcription factor, which in turn, potentiates and reinforces the regulatory effects of the miRs on Vegfa to trigger and sustain a significant physiological response. In humans, the miR-17 family is composed of six distinct mature miRs located on three chromosomes: miR-17-5p and miR-20a are located on chromosome 13q31.3, miR-20b and miR106a are located on chromosome Xq26.2, and miR-106b and miR-93 are located on chromosome 7q22.1. Members of this family seem to be derived from gene duplication events (9), and despite some divergences in length and nucleotide composition, their seed sequence (AAAGUG) is identical, an attribute suggestive of functional redundancy (10). Although the miR-17-92 cluster has been well-characterized, the regulatory role of the miR-17 family members has not been extensively studied (11,12). Distinct prediction algorithms (13-16) indicate that the miR-17 miR family may target the 3′ UTRs of genes encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. 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 (17-19).Here, we show the synchronous down-regulation of all members of the miR-17 family in the critical early steps of neovascularization in the ROP model. We propose an miR regulatory network, in which distinct and partially redundant miR-17 family members simultaneously affect the levels of the Hif1a transcription factor to posttranscriptionally (either directly and/or indirectly) increase the expres...

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MicroRNAs Regulate Ocular Neovascularization

Cited by 195 publications

References 46 publications

Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization

Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization

miR-376b-5p regulates angiogenesis in cerebral ischemia

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

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