title: MicroRNA-10 regulates the angiogenic behavior of zebrafish and human endothelial cells by promoting vascular endothelial growth factor signaling.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. david.hassel@med.uni-heidelberg.de
authors.forename: David
authors.initials: D
authors.lastname: Hassel
authors.forename: Paul
authors.initials: P
authors.lastname: Cheng
authors.forename: Mark P
authors.initials: MP
authors.lastname: White
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: Ivey
authors.forename: Jens
authors.initials: J
authors.lastname: Kroll
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007814:Larva / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish
chemical_list: C547183:MIRN10 microRNA, human; C577984:MIRN10 microRNA, zebrafish; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2