Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Co-Ordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor
Background—In infarcted heart, improper clearance of dying cells by activated neighbouring phagocytes may precipitate the transition to heart failure. We analysed the coordinated role of two major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction (MI).
Methods and Results—We generated double deficient mice for Mertk and Mfge8 (Mertk-/-/Mfge8-/-) and challenged them with acute coronary ligature. Compared to wild-type (WT), Mertk (Mertk-/-) or Mfge8 (Mfge8-/-) deficient animals, Mertk-/-/Mfge8-/- mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were mainly expressed by cardiac Ly6CHigh and low monocytes and macrophages. In parallel, Mertk-/-/Mfge8-/- bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area and larger infarct size as well as reduced angiogenesis. We found that the abrogation of efferocytosis impacted neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6Chigh and Ly6Clow monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6Chigh /Ly6Clow monocytes/macrophages obtained from either in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted VEGFA release. Using LysMCre+/VEGFAfl/fl mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis.
Conclusions—Following MI, Mertk and Mfge8- expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes favoring the secretion of VEGFA to locally repair the dysfunctional heart.
- Received December 15, 2015.
- Revision received January 21, 2016.
- Accepted January 22, 2016.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.