Journal
CIRCULATION RESEARCH
Volume 111, Issue 11, Pages 1421-U163Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.112.279711
Keywords
angiogenesis; developmental biology; fms-related tyrosine kinase 1; microRNA; vascular endothelial growth factor
Funding
- Deutsche Forschungsgemeinschaft [HA 5819/1-1]
- German Center for Cardiovascular Diseases (DZHK)
- American Heart Association
- California Institute for Regenerative Medicine (CIRM)
- National Institutes of Health (NIH) [HL54737]
- Packard Foundation
- National Heart, Lung, and Blood Institute/NIH [U01 HL100406]
- CIRM
- William Younger Family Foundation
- L.K. Whittier Foundation
- Roddenberry Foundation
- NIH National Institute of General Medical Sciences [T32 GMO7618]
- Medical Scientist Training Program (MSTP)
- NIH/National Center for Research Resources grant [C06 RR018928]
- Deutsche Forschungsgemeinschaft SFB-TR23 Vascular Differentiation and Remodeling [A3, Z5]
- Aventis Foundation
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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. (Circ Res. 2012;111:1421-1433.)
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