MicroRNA-214 inhibits angiogenesis by targeting Quaking and reducing angiogenic growth factor release.
OBJECTIVE
Angiogenesis is a critical component of many pathological conditions in adult tissues and is essential for embryonic development. MicroRNAs are indispensable for normal vascular development, but their exact role in regulating angiogenesis remains unresolved. Previously, we have observed that miR-214 is differentially expressed in compensatory arteriogenesis. Here, we investigated the potential role of miR-214 in the process of angiogenesis.


RESULTS
miR-214 is expressed in all major vascular cell types, and modulation of miR-214 levels in endothelial cells significantly affected tubular sprouting. In vivo silencing of miR-214 enhanced the formation of a perfused vascular network in implanted Matrigel plugs and retinal developmental angiogenesis in mice. miR-214 directly targets Quaking, a protein critical for vascular development. Quaking knockdown reduced pro-angiogenic growth factor expression and inhibited endothelial cell sprouting similar to miR-214 overexpression. In accordance, silencing of miR-214 increased the secretion of pro-angiogenic growth factors, including vascular endothelial growth factor, and enhanced the pro-angiogenic action of the endothelial cell-derived conditioned medium, whereas miR-214 overexpression had the opposite effect.


CONCLUSIONS
Here, we report a novel role for miR-214 in regulating angiogenesis and identify Quaking as a direct target of miR-214. The anti-angiogenic effect of miR-214 is mediated through the down-regulation of Quaking and pro-angiogenic growth factor expression. This study presents miR-214 as a potential important target for pro- or anti-angiogenic therapies.
Division of Heart and Lungs, Department of Cardiology,  University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, 3584 CX Utrecht,  the Netherlands.
Alain
A
van Mil
Sebastian
S
Grundmann
Marie-José
MJ
Goumans
Zhiyong
Z
Lei
Martinus I
MI
Oerlemans
Sridevi
S
Jaksani
Pieter A
PA
Doevendans
Joost P G
JP
Sluijter
D042501:Angiogenic Proteins / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012171:Retinal Vessels / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042501:Angiogenic Proteins; D035683:MicroRNAs; C534781:Mirn214 microRNA, mouse; D010982:Platelet-Derived Growth Factor; C098217:Qk protein, mouse; D016601:RNA-Binding Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2