Abstract
SUMMARYDespite 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.
Highlights
Acute cardiac ischemic injury [ known as myocardial infarction (MI)] afflicts about 1.5 million people in the USA every year and is a leading cause of mortality, accounting for one in every four deaths
Our results suggest that canonical Wnt signaling is involved in endothelial-to-mesenchymal transition (EndMT) after ischemic injury and that this process might be a key contributor to new endothelial cells and myofibroblasts during granulation tissue formation
Expression of Wnt pathway mediators is induced after experimental MI To evaluate the response of Wnt pathway components to myocardial ischemic injury, we permanently occluded the left anterior descending (LAD) coronary artery of C57BL/6J mice
Summary
Acute cardiac ischemic injury [ known as myocardial infarction (MI)] afflicts about 1.5 million people in the USA every year and is a leading cause of mortality, accounting for one in every four deaths. The widespread cell death causes an immediate and massive inflammatory response that gradually clears out the injury site, leaving behind sparse tissue with enlarged capillaries. After cellular debris is removed from the injury area, the gap fills with granulation tissue. This process starts a few days after the initial ischemic assault and involves activation and proliferation of endothelial cells and infiltration of myofibroblasts (Frangogiannis, 2008). Angiogenesis leads to the formation of new vessels in an attempt to restore blood
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