miR-184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways.
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.
Department of Dermatology Northwestern University, Chicago, Illinois, USA.
Jong Kook
JK
Park
Department of Dermatology Northwestern University, Chicago, Illinois, USA.
Han
H
Peng
Department of Dermatology Northwestern University, Chicago, Illinois, USA.
Wending
W
Yang
Department of Dermatology, New York Metropolitan Hospital, New York, New York, USA; and.
Julia
J
Katsnelson
Department of Urology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Olga
O
Volpert
Department of Dermatology Northwestern University, Chicago, Illinois, USA; r-lavker@northwestern.edu.
Robert M
RM
Lavker
D043925:Angiogenesis Inducing Agents; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D043925:Angiogenesis Inducing Agents; D004268:DNA-Binding Proteins; C534424:MIRN184 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt
FOG2; PDGF-β; PPAP2B; corneal epithelium; limbal epithelium