MicroRNA-10 regulates the angiogenic behavior of zebrafish and human endothelial cells by promoting vascular endothelial growth factor signaling.
RATIONALE: Formation and remodeling of the vasculature during development and disease involve a highly conserved and precisely regulated network of attractants and repellants. Various signaling pathways control the behavior of endothelial cells, but their posttranscriptional dose titration by microRNAs is poorly understood. OBJECTIVE: To identify microRNAs that regulate angiogenesis. METHODS AND RESULTS: We show that the highly conserved microRNA family encoding miR-10 regulates the behavior of endothelial cells during angiogenesis by positively titrating proangiogenic signaling. Knockdown of miR-10 led to premature truncation of intersegmental vessel growth in the trunk of zebrafish larvae, whereas overexpression of miR-10 promoted angiogenic behavior in zebrafish and cultured human umbilical venous endothelial cells. We found that miR-10 functions, in part, by directly regulating the level of fms-related tyrosine kinase 1 (FLT1), a cell-surface protein that sequesters vascular endothelial growth factor, and its soluble splice variant sFLT1. The increase in FLT1/sFLT1 protein levels upon miR-10 knockdown in zebrafish and in human umbilical venous endothelial cells inhibited the angiogenic behavior of endothelial cells largely by antagonizing vascular endothelial growth factor receptor 2 signaling. CONCLUSIONS: Our study provides insights into how FLT1 and vascular endothelial growth factor receptor 2 signaling is titrated in a microRNA-mediated manner and establishes miR-10 as a potential new target for the selective modulation of angiogenesis.
Pubmed ID: 22955733 RIS Download
Animals | Animals, Genetically Modified | Base Sequence | Cell Proliferation | Cells, Cultured | Endothelial Cells | Female | Gene Knockdown Techniques | Green Fluorescent Proteins | Human Umbilical Vein Endothelial Cells | Humans | Immunoblotting | Larva | Male | Mice | MicroRNAs | Microscopy, Confocal | Neovascularization, Physiologic | Reverse Transcriptase Polymerase Chain Reaction | Sequence Homology, Nucleic Acid | Signal Transduction | Vascular Endothelial Growth Factor A | Vascular Endothelial Growth Factor Receptor-1 | Vascular Endothelial Growth Factor Receptor-2 | Zebrafish