The microRNA miR-199a-5p down-regulation switches on wound angiogenesis by derepressing the v-ets erythroblastosis virus E26 oncogene homolog 1-matrix metalloproteinase-1 pathway

J Biol Chem. 2012 Nov 30;287(49):41032-43. doi: 10.1074/jbc.M112.413294. Epub 2012 Oct 11.


miR-199a-5p plays a critical role in controlling cardiomyocyte survival. However, its significance in endothelial cell biology remains ambiguous. Here, we report the first evidence that miR-199a-5p negatively regulates angiogenic responses by directly targeting v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1). Induction of miR-199a-5p in human dermal microvascular endothelial cells (HMECs) blocked angiogenic response in Matrigel® culture, whereas miR-199a-5p-deprived cells exhibited enhanced angiogenesis in vitro. Bioinformatics prediction and miR target reporter assay recognized Ets-1 as a novel direct target of miR-199a-5p. Delivery of miR-199a-5p blocked Ets-1 expression in HMECs, whereas knockdown endogenous miR-199a-5p induced Ets-1 expression. Matrix metalloproteinase 1 (MMP-1), one of the Ets-1 downstream mediators, was negatively regulated by miR-199a-5p. Overexpression of Ets-1 not only rescued miR-199a-5p-dependent anti-angiogenic effects but also reversed miR-199a-5p-induced loss of MMP-1 expression. Similarly, Ets-1 knockdown blunted angiogenic response and induction of MMP-1 in miR-199a-5p-deprived HMECs. Examination of cutaneous wound dermal tissue revealed a significant down-regulation of miR-199a-5p expression, which was associated with induction of Ets-1 and MMP-1. Mice carrying homozygous deletions in the Ets-1 gene exhibited blunted wound blood flow and reduced abundance of endothelial cells. Impaired wound angiogenesis was associated with compromised wound closure, insufficient granulation tissue formation, and blunted induction of MMP-1. Thus, down-regulation of miR-199a-5p is involved in the induction of wound angiogenesis through derepressing of the Ets-1-MMP1 pathway.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Cell Movement
  • Down-Regulation*
  • Endothelial Cells / cytology
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Male
  • Matrix Metalloproteinase 1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • Microcirculation
  • Models, Biological
  • Neovascularization, Physiologic*
  • Proto-Oncogene Protein c-ets-1 / metabolism
  • Proto-Oncogene Protein c-ets-1 / physiology*
  • Skin / pathology
  • Wound Healing*


  • ETS1 protein, human
  • MicroRNAs
  • Proto-Oncogene Protein c-ets-1
  • mirn199 microRNA, human
  • Matrix Metalloproteinase 1