title: miRNA-dependent cross-talk between VEGF and Ang-2 in hypoxia-induced microvascular dysfunction.
abstract: Ocular neovascularization is a vision-threatening complication of ischemic retinopathy that develops in various ocular disorders, such as retinopathy of prematurity (ROP) and diabetic retinopathy. Both Ang-2 and VEGF are implicated in this pathogenesis. However, their inter-regulation still remains elusive. Competitive endogenous RNAs (ceRNAs) are messenger RNA (mRNA) molecules that affect each other expression through the competition for the shared miRNA. Herein, we assessed whether the expression of Ang-2 and VEGF is interdependent through the sequestration of common miRNAs. Bioinformatics prediction and 3'-UTR luciferase assay revealed that Ang-2 and VEGF is commonly targeted by miR-351. Silencing either Ang-2 or VEGF increases the availabilities of shared miR-351, therefore reduces the activity of Luc-Ang-2 3'-UTR. The interdependence of VEGF and Ang-2 is miRNA- and 3'-UTR dependent, as silencing Dicer abolishes the interdependence. We also found that miR-351 dependency of VEGF-Ang-2 crosstalk occurs in retinal endothelial cells and rat retinas. miR-351 over-expression significantly reduces the level of VEGF and Ang-2 expression in vivo and in vitro. Overall, miRNA-dependent crosstalk between Ang-2 and VEGF plays a role in hypoxia-induced microvascular response. miRNA-based therapy can affect the expression of Ang-2 and VEGF, which represents a therapeutic potential for the treatment of vascular disease.
authors.affiliation: Department of Pediatrics, Zhongda Hospital, Southeast University, China.
authors.forename: Ruibin
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Zhongda Hospital, Southeast University, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Pediatrics, Zhongda Hospital, Southeast University, China. Electronic address: jiangli77777@126.com.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
mesh_terms: D020413:3' Untranslated Regions; D042702:Angiopoietin-2 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008253:Macaca mulatta; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D042702:Angiopoietin-2; C580764:MIRN351 microRNA, 351; D035683:MicroRNAs; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D008156:Luciferases; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: Ang-2; Hypoxia; VEGF; ceRNA; miRNA