miR-126 Regulation of Angiogenesis in Age-Related Macular Degeneration in CNV Mouse Model

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Abstract

miR-126 has recently been implicated in modulating angiogenic factors in vascular development. Understandings its biological significance might enable development of therapeutic interventions for diseases like age-related macular degeneration (AMD). We aimed to determine the role of miR-126 in AMD using a laser-induced choroidal neovascularization (CNV) mouse model. CNV was induced by laser photocoagulation in C57BL/6 mice. The CNV mice were transfected with scrambled miR or miR-126 mimic. The expression of miR-126, vascular endothelial growth factor-A (VEGF-A), Kinase insert domain receptor (KDR) and Sprouty-related EVH1 domain-containing protein 1 (SPRED-1) in ocular tissues were analyzed by qPCR and Western blot. The overexpression effects of miR-126 were also proven on human microvascular endothelial cells (HMECs). miR-126 showed a significant decrease in CNV mice ( p < 0.05). Both mRNA and protein levels of VEGF-A, KDR and SPRED-1 were upregulated with CNV; these changes were ameliorated by restoration of miR-126 ( p < 0.05). CNV was reduced after miR-126 transfection. Transfection of miR-126 reduced the HMECs 2D-capillary-like tube formation ( p < 0.01) and migration ( p < 0.01). miR-126 has been shown to be a negative modulator of angiogenesis in the eye. All together these results high lights the therapeutic potential of miR-126 suggests that it may contribute as a putative therapeutic target for AMD in humans.

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Control of translation and mRNA degradation by miRNAs and siRNAs.

Marco Antonio Valencia-Sanchez, Jidong Liu, Gregory J Hannon … (2006)

The control of translation and mRNA degradation is an important part of the regulation of gene expression. It is now clear that small RNA molecules are common and effective modulators of gene expression in many eukaryotic cells. These small RNAs that control gene expression can be either endogenous or exogenous micro RNAs (miRNAs) and short interfering RNAs (siRNAs) and can affect mRNA degradation and translation, as well as chromatin structure, thereby having impacts on transcription rates. In this review, we discuss possible mechanisms by which miRNAs control translation and mRNA degradation. An emerging theme is that miRNAs, and siRNAs to some extent, target mRNAs to the general eukaryotic machinery for mRNA degradation and translation control.

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miR-126 regulates angiogenic signaling and vascular integrity.

Jason Fish, Massimo M. Santoro, Sarah Morton … (2008)

Precise regulation of the formation, maintenance, and remodeling of the vasculature is required for normal development, tissue response to injury, and tumor progression. How specific microRNAs intersect with and modulate angiogenic signaling cascades is unknown. Here, we identified microRNAs that were enriched in endothelial cells derived from mouse embryonic stem (ES) cells and in developing mouse embryos. We found that miR-126 regulated the response of endothelial cells to VEGF. Additionally, knockdown of miR-126 in zebrafish resulted in loss of vascular integrity and hemorrhage during embryonic development. miR-126 functioned in part by directly repressing negative regulators of the VEGF pathway, including the Sprouty-related protein SPRED1 and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-beta). Increased expression of Spred1 or inhibition of VEGF signaling in zebrafish resulted in defects similar to miR-126 knockdown. These findings illustrate that a single miRNA can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.

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Role of microRNAs in vascular diseases, inflammation, and angiogenesis.

Carmen Urbich, Angelika Kuehbacher, Stefanie Dimmeler (2008)

The integrity of the endothelial monolayer is fundamental for the homoeostasis of the vascular system. Functional endothelial cells are also required for the growth of new blood vessels during neovascularization. Although multiple growth factors have been shown to regulate angiogenesis and vascular development, little is known about the complex upstream regulation of gene expression and translation. MicroRNAs (miRNAs) are an emerging class of highly conserved, non-coding small RNAs that regulate gene expression on the post-transcriptional level by inhibiting the translation of protein from mRNA or by promoting the degradation of mRNA. More than 500 human miRNAs have been identified so far, and increasing evidence indicates that miRNAs have distinct expression profiles and play crucial roles in various physiological and pathological processes such as cardiogenesis, haematopoietic lineage differentiation, and oncogenesis. Meanwhile, a few specific miRNAs that regulate endothelial cell functions and angiogenesis have been described. Let7-f, miR-27b, and mir-130a were identified as pro-angiogenic miRNAs. In contrast, miR-221 and miR-222 inhibit endothelial cell migration, proliferation, and angiogenesis in vitro by targeting the stem cell factor receptor c-kit and indirectly regulating endothelial nitric oxide synthase expression. Moreover, some miRNAs are involved in tumour angiogenesis such as the miR-17-92 cluster and miR-378. Early studies also indicate the contribution of specific miRNAs (e.g. miR-155, miR-21, and miR-126) to vascular inflammation and diseases. Thus, the identification of miRNAs and their respective targets may offer new therapeutic strategies to treat vascular diseases such as atherosclerosis, to improve neovascularization after ischaemia, or to prevent tumour progression.

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Y-h. Taguchi: Role: Academic Editor

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 07 June 2016

Publication date Collection: June 2016

Volume: 17

Issue: 6

Electronic Location Identifier: 895

Affiliations

[1 ]Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin 150001, China; wangleiPHD@ 123456126.com

[2 ]Department of Pharmacology and Therapeutics, Drug Delivery Unit, Centre for Eye Research Australia, University of Melbourne, East Melbourne VIC 3000, Australia; amylee1192@ 123456gmail.com

[3 ]Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, East Melbourne VIC 3000, Australia; jonathanwigg@ 123456outlook.com (J.P.W.); hiteshp@ 123456163.com (H.P.)

Author notes

[* ]Correspondence: pingliu53@ 123456126.com (P.L.); hong.zhang@ 123456unimelb.edu.au (H.Z.); Tel.: +86-451-8555-3927 (P.L.); +61-3-9288-3721 (H.Z.); Fax: +86-451-8555-3921 (P.L.); +61-3-9662-3859 (H.Z.)

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Publisher ID: ijms-17-00895

DOI: 10.3390/ijms17060895

PMC ID: 4926429

PubMed ID: 27338342

SO-VID: 21b197fb-ad8c-4b90-95b3-de187042fd13

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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

miR-126 Regulation of Angiogenesis in Age-Related Macular Degeneration in CNV Mouse Model

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Karger: Ophthalmology

Most cited references 49

Control of translation and mRNA degradation by miRNAs and siRNAs.

miR-126 regulates angiogenic signaling and vascular integrity.

Role of microRNAs in vascular diseases, inflammation, and angiogenesis.

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