Experimental myocardial infarction triggers canonical Wnt signaling and endothelial-to-mesenchymal transition

Dis Model Mech. 2011 Jul;4(4):469-83. doi: 10.1242/dmm.006510. Epub 2011 Feb 14.

Abstract

Despite available therapies, myocardial infarction (MI) remains a leading cause of death worldwide. Better understanding of the molecular and cellular mechanisms that regulate cardiac repair should help to improve the clinical outcome of MI patients. Using the reporter mouse line TOPGAL, we show that canonical (β-catenin-dependent) Wnt signaling is induced 4 days after experimental MI in subepicardial endothelial cells and perivascular smooth muscle actin (SMA)-positive (SMA(+)) cells. At 1 week after ischemic injury, a large number of canonical-Wnt-positive cells accumulated in the infarct area during granulation tissue formation. Coincidently with canonical Wnt activation, endothelial-to-mesenchymal transition (EndMT) was also triggered after MI. Using cell lineage tracing, we show that a significant portion of the canonical-Wnt-marked SMA(+) mesenchymal cells is derived from endothelial cells. Canonical Wnt signaling induces mesenchymal characteristics in cultured endothelial cells, suggesting a direct role in EndMT. In conclusion, our study demonstrates that canonical Wnt activation and EndMT are molecular and cellular responses to MI and that canonical Wnt signaling activity is a characteristic property of EndMT-derived mesenchymal cells that take part in cardiac tissue repair after MI. These findings could lead to new strategies to improve the course of cardiac repair by temporal and cell-type-specific manipulation of canonical Wnt signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Blood Vessels / metabolism
  • Blood Vessels / pathology
  • Cells, Cultured
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Endothelium / metabolism
  • Endothelium / pathology*
  • Granulation Tissue / metabolism
  • Granulation Tissue / pathology
  • Heart Valves / metabolism
  • Heart Valves / pathology
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mesoderm / metabolism
  • Mesoderm / pathology*
  • Mice
  • Models, Biological
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / pathology*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Signal Transduction*
  • Wnt Proteins / metabolism*

Substances

  • Actins
  • Intercellular Signaling Peptides and Proteins
  • Wnt Proteins
  • alpha-smooth muscle actin, mouse