|ZFIN ID: ZDB-PUB-120909-4|
|Source:||Circulation research 111(11): 1421-1433 (Journal)|
|Registered Authors:||Hassel, David, Stainier, Didier|
|Keywords:||angiogenesis, development, microRNA, vascular endothelial growth factor, fms-related tyrosine kinase 1, developmental biology|
Animals; Animals, Genetically Modified; Base Sequence; Cell Proliferation/drug effects; Cells, Cultured
|PubMed:||22955733 Full text @ Circ. Res.|
Rationale: Formation and remodeling of the vasculature during development and disease involves a highly conserved and precisely regulated network of attractants and repellants. Various signaling pathways control the behavior of endothelial cells, but their post-transcriptional dose-titration by miRNAs is poorly understood.
Objective: To identify miRNAs 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 pro-angiogenic signaling. Knockdown of miR-10 led to premature truncation of intersegmental vessel growth (ISV) in the trunk of zebrafish larvae, while overexpression of miR-10 promoted angiogenic behavior in zebrafish and cultured human umbilical venous endothelial cells (HUVECs). 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 VEGF, and its soluble splice variant sFLT1. The increase in FLT1/sFLT1 protein levels upon miR-10 knockdown in zebrafish and in HUVECs inhibited the angiogenic behavior of endothelial cells largely by antagonizing VEGF receptor-2 signaling.
Conclusions: Our study provides insights into how FLT1 and VEGF receptor-2 signaling is titrated in a miRNA-mediated manner and establishes miR-10 as a potential new target for the selective modulation of angiogenesis.