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ZFIN ID: ZDB-PUB-120909-4
MicroRNA-10 Regulates the Angiogenic Behavior of Zebrafish and Human Endothelial Cells by Promoting Vascular Endothelial Growth Factor Signaling
Hassel, D., Cheng, P., White, M.P., Ivey, K.N., Kroll, J., Augustin, H.G., Katus, H.A., Stainier, D.Y., and Srivastava, D.
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.