MicroRNAs in Vascular Eye Diseases

Abstract

Since the discovery of the first microRNA (miRNA) decades ago, studies of miRNA biology have expanded in many biomedical research fields, including eye research. The critical roles of miRNAs in normal development and diseases have made miRNAs useful biomarkers or molecular targets for potential therapeutics. In the eye, ocular neovascularization (NV) is a leading cause of blindness in multiple vascular eye diseases. Current anti-angiogenic therapies, such as anti-vascular endothelial growth factor (VEGF) treatment, have their limitations, indicating the need for investigating new targets. Recent studies established the roles of various miRNAs in the regulation of pathological ocular NV, suggesting miRNAs as both biomarkers and therapeutic targets in vascular eye diseases. This review summarizes the biogenesis of miRNAs, and their functions in the normal development and diseases of the eye, with a focus on clinical and experimental retinopathies in both human and animal models. Discovery of novel targets involving miRNAs in vascular eye diseases will provide insights for developing new treatments to counter ocular NV.

Keywords: AMD: biomarker; eye disease; microRNA; neovascularization; retinopathy.

Figure 1

MicroRNA (miRNA) biogenesis. This schematic diagram illustrates the canonical pathway of miRNA biogenesis. The miRNA gene is transcribed by RNA polymerase II (Poly II) to generate the primary miRNA (pri-miRNA) that forms hairpin structures. The long pri-miRNA is then processed by Drosha and DiGeorge syndrome critical region 8 (DGCR8) into the shorter precursor miRNA (pre-miRNA), which is then exported to the cytosol with the help of exportin-5. The pre-miRNA is further cleaved by Dicer and transactivation response element RNA-binding protein (TRBP), yielding the miRNA:miRNA* duplex molecule, which is loaded into argonaute (AGO) to unwind and form the functional RNA-induced silencing complex (RISC). The mature miRNA then binds to the seed sequences on the 3′ untranslated region (3′UTR) of the target mRNA, leading to its translation repression or cleavage and thereby degradation.

Figure 2

The anatomy of the eye and relevant miRNAs. (A) The schematic diagram illustrates the main structures of the human eye. (B) The schematic representation of the cell types in the neural retina depicts their cellular connections (including ganglion cells, amacrine cells, bipolar cells, horizontal cells, as well as rod and cone photoreceptors) and supporting cells (Müller cells and RPE). (C) A cross section of the eye shows the laminar organization of the nuclear layers (GCL, INL, and ONL), the retinal vasculature, and segments of photoreceptors (IS/OS). The RPE monolayer, with Bruch’s membrane underneath, is located between the neural retina and the choroid complex. miRNAs that regulate the physiological functions or pathological conditions related to each retinal neuronal and vessel layers, and RPE, are listed next to respective histological structure. Deep, deep layer of retinal vessels; GCL, ganglion cell layer; INL, inner nuclear layer; Int, intermediate layer of retinal vessels; IS/OS, inner/outer segments; ONL, outer nuclear layer; RPE, retinal pigment epithelium; Sup, superficial layer of retinal vessels. Figure adapted from “Animal models of ocular angiogenesis: from development to pathologies” by Liu et al. 2017, FASEB J, 31(11), p. 4665–4681 [57].

Figure 3

Targeting miR-150 and miR-145 in experimental retinopathy. This illustration uses miR-150 and miR-145 as the two examples to depict the effects of miRNAs on normal and pathological ocular angiogenesis. In normal retinal vessels, the endothelial-enriched miR-150 suppresses expression of its downstream angiogenic genes, such as Cxcr4, Dll4, and Fzd4, resulting in reduced angiogenic effects. On the other hand, normal endothelial cells have low levels of miR-145, which induces target gene TMOD3, allowing its binding to the pointed end of acting filaments, stabilizing the cytoplasmic actin mesh. High levels of miR-150 and low levels of miR-145 in normal retinal vessels both function to maintain quiescence of retinal vessels. On the other hand, in retinopathy, decreased expression levels of miR-150 in pathological neovessels results in upregulation of its angiogenic targets—CXCR4, DLL4, and FZD4, leading to increased angiogenesis and formation of pathologic neovascularization. Retinal hypoxia in the retinopathy condition also causes the upregulation of miR-145, leading to repression of Tmod3, releasing the capping of actin filaments. This alteration in actin dynamics and architecture leads to increased endothelial cell angiogenic function, and thereby enhanced pathological angiogenesis. Figure adapted from “Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization” by Liu et al. 2015, PNAS, 112(39), p. 12163–12168 [169]; and “MicroRNA-145 Regulates Pathological Retinal Angiogenesis by Suppression of TMOD3” by Liu et al. 2019, Mol Ther Nucleic Acids, 16, p. 335–347 [168].