Macrophages have been suggested to be beneficial for myocardial wound healing. We investigated the role of macrophages in myocardial wound healing by inhibition of macrophage infiltration after myocardial injury. We used a murine cryoinjury model to induce left ventricular damage. Infiltrating macrophages were depleted during the 1st week after cryoinjury by serial intravenous injections of clodronate-containing liposomes. After injury, the presence of macrophages, which secreted high levels of transforming growth factor-beta and vascular endothelial growth factor-A, led to rapid removal of cell debris and replacement by granulation tissue containing inflammatory cells and blood vessels, followed by myofibroblast infiltration and collagen deposition. In macrophage-depleted hearts, nonresorbed cell debris was still observed 4 weeks after injury. Secretion of transforming growth factor-beta and vascular endothelial growth factor-A as well as neovascularization, myofibroblast infiltration, and collagen deposition decreased. Moreover, macrophage depletion resulted in a high mortality rate accompanied by increased left ventricular dilatation and wall thinning. In conclusion, infiltrating macrophage depletion markedly impairs wound healing and increases remodeling and mortality after myocardial injury, identifying the macrophage as a key player in myocardial wound healing. Based on these findings, we propose that increasing macrophage numbers early after myocardial infarction could be a clinically relevant option to promote myocardial wound healing and subsequently to reduce remodeling and heart failure.

Atherosclerosis is an inflammatory disease resulting in the hardening and thickening of the wall of arteries and the formation of plaques, which comprise immune cells, mesenchymal cells, lipids, and extracellular matrix. The source of mesenchymal cells in the atherosclerotic plaques has been under scrutiny for years. Current endothelial-lineage tracing studies indicate that the endothelium is a source for plaque-associated mesenchymal cells. Endothelial cells can acquire a mesenchymal phenotype through endothelial-mesenchymal transition (EndMT), wherein the expression of endothelial markers and functions is lost and the expression of mesenchymal cell marker and functions acquired. Furthermore, EndMT can result in delamination and migration of endothelial cell-derived mesenchymal cells into the underlying tissue. Here, we review the contribution of EndMT in vascular disease focusing on atherosclerosis and describe the major biochemical and biomechanical signalling pathways in EndMT during atherosclerosis progression. Furthermore, we address how the well-established systemic atherosclerosis risk factors might facilitate EndMT during atherosclerosis.