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Circ Res. 2012 Nov 9;111(11):1421-33. doi: 10.1161/CIRCRESAHA.112.279711. Epub 2012 Sep 5.

MicroRNA-10 regulates the angiogenic behavior of zebrafish and human endothelial cells by promoting vascular endothelial growth factor signaling.

Author information

1
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. david.hassel@med.uni-heidelberg.de

Abstract

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.

PMID:
22955733
PMCID:
PMC3525481
DOI:
10.1161/CIRCRESAHA.112.279711
[Indexed for MEDLINE]
Free PMC Article

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