MicroRNA-10 Regulates the Angiogenic Behavior of Zebrafish and Human Endothelial Cells by Promoting Vascular Endothelial Growth Factor Signaling
- Authors
- Hassel, D., Cheng, P., White, M.P., Ivey, K.N., Kroll, J., Augustin, H.G., Katus, H.A., Stainier, D.Y., and Srivastava, D.
- ID
- ZDB-PUB-120909-4
- Date
- 2012
- Source
- Circulation research 111(11): 1421-1433 (Journal)
- Registered Authors
- Hassel, David, Kroll, Jens, Stainier, Didier
- Keywords
- angiogenesis, development, microRNA, vascular endothelial growth factor, fms-related tyrosine kinase 1, developmental biology
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Base Sequence
- Cell Proliferation/drug effects
- Cells, Cultured
- Endothelial Cells/metabolism*
- Female
- Gene Knockdown Techniques
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Human Umbilical Vein Endothelial Cells/metabolism
- Humans
- Immunoblotting
- Larva/genetics
- Larva/metabolism
- Male
- Mice
- MicroRNAs/genetics*
- Microscopy, Confocal
- Neovascularization, Physiologic/genetics*
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Homology, Nucleic Acid
- Signal Transduction/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Vascular Endothelial Growth Factor A/pharmacology
- Vascular Endothelial Growth Factor Receptor-1/genetics*
- Vascular Endothelial Growth Factor Receptor-1/metabolism
- Vascular Endothelial Growth Factor Receptor-2/genetics*
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Zebrafish
- 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.