Mirtron microRNA-1236 inhibits VEGFR-3 signaling during inflammatory lymphangiogenesis.
OBJECTIVE
Vascular endothelial growth factor receptor(VEGFR)-3 is a critical regulator of developmental and adult vasculogenesis and lymphangiogenesis through its interactions with select members of the VEGF family. The goal of this study was to investigate how VEGFR-3 expression is regulated during inflammatory lymphangiogenesis.


RESULTS
In this study, we present for the first time evidence that VEGFR-3 can be negatively regulated by a mirtron, hsa-miR-1236 (miR-1236), which is expressed in primary human lymphatic endothelial cells. In human lymphatic endothelial cells, miR-1236 is upregulated in response to IL-1β, a negative regulator of VEGFR-3. miR-1236 binds the 3' untranslated region of Vegfr3, resulting in translational inhibition. Overexpression of miR-1236 significantly decreased expression of VEGFR-3, but not VEGFR-2, in human lymphatic endothelial cells. Compared to a control miR, overexpression of miR-1236 also led to decreased VEGFR-3 signaling. However, VEGFR-2-specific signaling was not affected. miR-1236 can attenuate human lymphatic endothelial cell migration and tube formation, as well as in vivo lymphangiogenesis.


CONCLUSIONS
Our data suggest that miR-1236 may function as a negative regulator of VEGFR-3 signaling during inflammatory lymphangiogenesis.
Interdepartmental Program in Vascular Biology and Therapeutics, Department of Immunobiology, Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520, USA.
Dennis
D
Jones
Yonghao
Y
Li
Yun
Y
He
Zhe
Z
Xu
Hong
H
Chen
Wang
W
Min
D020413:3' Untranslated Regions; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002465:Cell Movement; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D042583:Lymphangiogenesis / Q000235:genetics*; D042601:Lymphatic Vessels / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics*; D014162:Transfection; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics* / Q000378:metabolism
D020413:3' Untranslated Regions; D053583:Interleukin-1beta; C571208:MIRN1236 microRNA, human; D035683:MicroRNAs; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3