miR‐184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways

Abstract

Corneal avascularity is critical for achieving transparency necessary for proper transmission of light to the lens and visual acuity. Although much is known about angiogenesis and angiostasis, the precise regulation of these processes in the cornea is unclear. MicroRNA (miR)-184, the most abundant corneal epithelial miRNA, has been suggested to function in corneal angiostasis by altering VEGF signaling; however, the mechanism(s) underlying this regulation have not been addressed. Using a combination of in vitro and in vivo assays to evaluate angiogenesis, we demonstrated that human limbal epithelial keratinocytes (HLEKs) engineered to overexpress miR-184 secreted lower amounts of angiogenic mitogens. Human dermal microvascular cells exposed to conditioned medium from miR-184-overexpressing HLEKs were less proliferative and failed to seal linear scratch wounds. The in vivo Matrigel plug assay showed that conditioned medium from miR-184-expressing HLEKs elicited a lesser degree of neovascularization compared with controls. We found that miR-184 directly targets and represses the proangiogenic factors, friend of Gata 2 (FOG2), platelet-derived growth factor (PDGF)-β, and phosphatidic acid phosphatase 2b (PPAP2B). FOG2 regulates VEGF expression, whereas PDGF-β and PPAP2B regulate Akt activity. By attenuating both VEGF and Akt signaling, miR-184 acts as a broad-spectrum negative regulator of corneal angiogenesis.-Park, J. K., Peng, H., Yang, W., Katsnelson, J., Volpert, O., Lavker, R. M. miR-184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways.

Recent drug therapies for corneal neovascularization

“…Researches showed that miR‐184 can inhibit CNV by attenuating both VEGF and Akt signaling. It can suppress the proangiogenic factors, friend of Gata 2, phosphatidic acid phosphatase 2b and platelet‐derived growth factor (PDGF)‐β directly . However, there were experiments showing that the expression of miR‐21 increased significantly compared with the healthy cornea at 4 and 7 days after alkali burn.…”

Exosomes from normal and diabetic human corneolimbal keratocytes differentially regulate migration, proliferation and marker expression of limbal epithelial cells

“…Alternatively, downregulation of miR-4516, may present an attempt of the diabetic stromal cells to preserve normal wound healing, which may be eventually counteracted by other miRs that become elevated in diabetes, for instance, miR-146a that inhibits wound healing-stimulating EGFR 48 . Interestingly, miR-184, the most abundantly expressed miRNA in central corneal epithelium 49 , 50 is among the top differentially expressed miRNAs and is significantly upregulated in DM-Exos. Its key role in corneal epithelial homeostasis has been shown in several studies 50 – 52 .…”

Differential Expression of miRNAs in the Respiratory Tree of the Sea Cucumber Apostichopus japonicus Under Hypoxia Stress

“…For example, miR-184 negatively modulates Wnt signaling both in vivo and in vitro ( Takahashi et al 2015 ). MiR-184 could inhibit protein expression in human trabecular meshwork cell cytotoxicity, apoptosis, and extracellular matrix via targeting HIF-1α in vivo , and it can also exhibit angiostatic properties through regulating signaling pathways including Akt, TNF-α, and VEGF ( Park et al 2017 ; Wang et al 2017 ). All the results mentioned above showed that Aja-miR-184 may be crucial to the stress response in sea cucumbers by regulating genes related to autophagy, oxidative damage, and cell proliferation under hypoxia stress.…”