Ronald Alek Sperry

Backgound: Corneal neovascularization is a condition characterized by ingrowth of blood vessels into the corneal tissue. Currently, treatment is progression-dependent because immature blood vessels depend on growth factors for proliferation while established blood vessels do not. This dictates that treatment be aimed at either the removal of established vasculature or at the prevention of neo-angiogenesis via the targeting of these growth factors. In the latter, MEG3, a tumor suppressor gene, has recently been proposed as a potential target for knockdown due to its ability to combat the expression of several different proangiogenic factors.

Objective: In this review, we explore MEG3 and the mechanisms by which its knockdown can reduce corneal neovascularization

Search Methods: An online search in the PubMed database was performed and research selected between the years of 2016 to 2022 using the keywords ‘MEG3’, ‘corneal neovascularization’ and ‘angiogenesis’.

Results: Studies suggest that the MEG3 gene may exhibit tissue-specific effects that may be useful in the cornea due to its normally avascular state. In one instance, MEG3 was shown to influence sprouting angiogenesis in a recent study performed by Ruan et al., where MEG3 knockdown resulted in a significant reduction in sprouting angiogenesis via a reduction in VEGF release in HUVEC’s. VEGF release was shown to be mediated by TGF- β by Wang et al. in mouse retinal cells, where it stimulates serine/threonine kinase receptors that phosphorylate the SMAD2/3 pathway. Shen et al. studied these findings in the cornea by knocking down MEG3 in mice, resulting in a marked reduction of both SMAD2/3 phosphorylation and subsequent VEGF release. In addition, MEG3 knockdown was shown to have an effect in intussusceptive or “splitting” angiogenesis by Shen et al. via the reduction of SDF1 and CXCR4 expression on the surface of stabilizing mononuclear cells of rat corneal epithelium. These surface receptors were shown to be key mediators in intussusceptive angiogenesis by Dimova et al. in their study on mouse liver sinusoidal cells where treatment with recombinant SDF-1 resulted in a 4-fold increase in vascular intussusception.

Conclucsion: Studies show that MEG3 knockdown results in a decrease in sprouting angiogenesis in mouse corneal tissue via a decrease in expression of TGF- β mediated SMAD2/3 phosphorylation pathway induced VEGF release. It also decreased intussusceptive angiogenesis via a reduction in SDF-1/CXCR4 expression, which decreased the efficacy of monocyte stabilization. These findings suggest that MEG3 may be a suitable target for the treatment of corneal neo-angiogenesis.

Works Cited:

1. Shen T, Wu Y, Cai W, et al. LncRNA Meg3 knockdown reduces corneal neovascularization and VEGF-induced vascular endothelial angiogenesis via SDF-1/CXCR4 and Smad2/3 pathway. Exp Eye Res. 2022;222:109166. doi:10.1016/j.exer.2022.109166
2. Chen J, Liao L, Xu H, Zhang Z, Zhang J. Long non-coding RNA MEG3 inhibits neovascularization in diabetic retinopathy by regulating microRNA miR-6720-5p and cytochrome B5 reductase 2. Bioengineered. 2021;12(2):11872-11884. doi:10.1080/21655979.2021.2000721
3. Dimova I, Karthik S, Makanya A, et al. SDF-1/CXCR4 signaling is involved in blood vessel growth and remodeling by intussusception. J Cell Mol Med. 2019;23(6):3916-3926. doi:10.1111/jcmm.14269
4. Wang X, Ma W, Han S, et al. TGF-β participates in choroid neovascularization through Smad2/3-VEGF/TNF-α signaling in mice with Laser-induced wet age-related macular degeneration. Sci Rep. 2017;7(1):9672. Published 2017 Aug 29. doi:10.1038/s41598-017-10124-4
5. Ruan W, Zhao F, Zhao S, Zhang L, Shi L, Pang T. Knockdown of long noncoding RNA MEG3 impairs VEGF-stimulated endothelial sprouting angiogenesis via modulating VEGFR2 expression in human umbilical vein endothelial cells. Gene. 2018;649:32-39. doi:10.1016/j.gene.2018.01.072