miR-126 regulates angiogenic signaling and vascular integrity.
Precise regulation of the formation, maintenance, and remodeling of the vasculature is required for normal development, tissue response to injury, and tumor progression. How specific microRNAs intersect with and modulate angiogenic signaling cascades is unknown. Here, we identified microRNAs that were enriched in endothelial cells derived from mouse embryonic stem (ES) cells and in developing mouse embryos. We found that miR-126 regulated the response of endothelial cells to VEGF. Additionally, knockdown of miR-126 in zebrafish resulted in loss of vascular integrity and hemorrhage during embryonic development. miR-126 functioned in part by directly repressing negative regulators of the VEGF pathway, including the Sprouty-related protein SPRED1 and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-beta). Increased expression of Spred1 or inhibition of VEGF signaling in zebrafish resulted in defects similar to miR-126 knockdown. These findings illustrate that a single miRNA can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.
Fish
Jason E
JE
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
Santoro
Massimo M
MM
Morton
Sarah U
SU
Yu
Sangho
S
Yeh
Ru-Fang
RF
Wythe
Joshua D
JD
Ivey
Kathryn N
KN
Bruneau
Benoit G
BG
Stainier
Didier Y R
DY
Srivastava
Deepak
D
D000818:Animals; D001483:Base Sequence; D001808:Blood Vessels / Q000196:embryology* / Q000473:pathology; D019070:Cell Lineage; D004625:Embryo, Nonmammalian; D042783:Endothelial Cells / Q000166:cytology; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
C484962:Egfl7 protein, zebrafish; D035683:MicroRNAs; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; D019869:Phosphatidylinositol 3-Kinases