Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor

Background— In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 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. Methods and Results— We generated double-deficient mice for Mertk and Mfge8 (Mertk−/−/Mfge8−/−) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk−/−), or Mfge8-deficient (Mfge8−/−) animals, Mertk−/−/Mfge8−/− mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly 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 affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6CHigh and Ly6CHow monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6CHigh/Ly6CLow monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre+/VEGFAfl/fl mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. Conclusions— After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the dysfunctional heart.

• Publication year

  2016

• Venue

  Circulation

• Publication date

  2016-02-29

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1161/CIRCULATIONAHA.115.020857PMID 26819373PMCID 4767109
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Resolution of liver fibrosis requires myeloid cell–driven sinusoidal angiogenesis

  2015cited by this paper
• Impaired Clearance of Apoptotic Cells in Chronic Inflammatory Diseases: Therapeutic Implications

  2014cited by this paper
• Origin and functions of tissue macrophages.

  2014cited by this paper
• Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart

  2014cited by this paper
• Macrophage activation and polarization: nomenclature and experimental guidelines.

  2014cited by this paper
• Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution.

  2014cited by this paper
• Differential Contribution of Monocytes to Heart Macrophages in Steady-State and After Myocardial Infarction

  2014cited by this paper
• Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation.

  2014cited by this paper
• On-site education of VEGF-recruited monocytes improves their performance as angiogenic and arteriogenic accessory cells

  2013cited by this paper
• MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury.

  2013cited by this paper
• Angiogenesis in the Infarcted Myocardium

  2013influential reference
• Nr4a1-Dependent Ly6Clow Monocytes Monitor Endothelial Cells and Orchestrate Their Disposal

  2013cited by this paper
• B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction

  2013cited by this paper
• Enhanced Efferocytosis of Apoptotic Cardiomyocytes Through Myeloid-Epithelial-Reproductive Tyrosine Kinase Links Acute Inflammation Resolution to Cardiac Repair After Infarction

  2013cited by this paper
• Monocyte and Macrophage Heterogeneity in the Heart

  2013cited by this paper
• Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages

  2012cited by this paper
• The Chemokine Decoy Receptor D6 Prevents Excessive Inflammation and Adverse Ventricular Remodeling After Myocardial Infarction

  2012cited by this paper
• Macrophage plasticity and polarization: in vivo veritas.

  2012cited by this paper
• Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair

  2011cited by this paper
• Cell death in the pathogenesis of heart disease: mechanisms and significance.

  2010cited by this paper
• Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain–dependent manner

  2010cited by this paper
• Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

  2010cited by this paper
• Development of Monocytes, Macrophages, and Dendritic Cells

  2010cited by this paper
• Deletion of Vascular Endothelial Growth Factor in myeloid cells accelerates tumorigenesis

  2008cited by this paper
• Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial.

  2008cited by this paper
• Defective Mer Receptor Tyrosine Kinase Signaling in Bone Marrow Cells Promotes Apoptotic Cell Accumulation and Accelerates Atherosclerosis

  2008cited by this paper
• Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis

  2007cited by this paper
• Data Supplement (unedited) at:

  2007cited by this paper
• Essential role for MFG-E8 as ligand for alphavbeta5 integrin in diurnal retinal phagocytosis.

  2007cited by this paper
• The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions

  2007cited by this paper
• Death begets failure in the heart.

  2005cited by this paper
• CCL2/Monocyte Chemoattractant Protein-1 Regulates Inflammatory Responses Critical to Healing Myocardial Infarcts

  2005cited by this paper
• Lactadherin promotes VEGF-dependent neovascularization

  2005cited by this paper
• A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells.

  2005cited by this paper
• A role for Mer tyrosine kinase in αvβ5 integrin-mediated phagocytosis of apoptotic cells

  2005cited by this paper
• Autoimmune Disease and Impaired Uptake of Apoptotic Cells in MFG-E8-Deficient Mice

  2004cited by this paper
• Identification of mouse sperm SED1, a bimotif EGF repeat and discoidin-domain protein involved in sperm-egg binding.

  2003cited by this paper
• Identification of a factor that links apoptotic cells to phagocytes

  2002cited by this paper
• Phagocytosis and clearance of apoptotic cells is mediated by MER

  2001cited by this paper
• The Journal of Experimental Medicine

  2000cited by this paper
• Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.

  1998cited by this paper
• Cardiac specific expression of the green fluorescent protein during early murine embryonic development

  1998cited by this paper
• Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformation

  1997cited by this paper
• Integrative Physiology Methods and Results: We Show That Ly-6c Conclusions: Ly-6c Ly-6c High Monocytes Depend on Nr4a1 to Balance Both Inflammatory and Reparative Phases in the Infarcted Myocardium

  year unknowncited by this paper

• Eicosapentaenoic acid attenuates heart failure with preserved ejection fraction via promoting TREM2-dependent efferocytosis.

  2026cites this paper
• Spatial Transcriptional Heterogeneity in the Infarct Core and Its Surrounding Regions Targeting Piezo1 Signals in Rats With Myocardial Ischemia‐Reperfusion Injury

  2026cites this paper
• Extracellular BRICK1 drives heart repair after myocardial infarction in mice.

  2026cites this paper
• Macrophage Efferocytosis as a Therapeutic Strategy in Intervertebral Disc Degeneration

  2025cites this paper
• Cardiac macrophages and their functions in homeostasis and injury.

  2025cites this paper
• Efferocytosis in Homeostasis.

  2025cites this paper
• Macrophage-TREM2 promotes cardiac repair by restricting the infiltration of CD8+ T cells via CXCL16-CXCR6 axis after myocardial infarction

  2025cites this paper
• Macrophage metabolism in inflammatory heart disease: new insights and therapeutic implications

  2025cites this paper
• The Role of Neutrophil Extracellular Networks in Cardiovascular Pathology

  2025cites this paper
• Efferocytosis: the art of cellular clearance and novel perspectives in disease therapy

  2025cites this paper
• MFG-E8 in Kawasaki Disease: Role in Endothelial Injury and Diagnostic Potential

  2025cites this paper
• Macrophage ITGAV is dispensable for post-infarction remodeling in mice and does not mediate fibronectin responses

  2025cites this paper
• Inflammation-resolution signalling in cardiac repair, remodelling, and heart failure

  2025cites this paper
• The dual role of ATF3 in myocardial repair through macrophage regulation

  2025cites this paper
• Exploring the Cardioprotective Mechanisms of Ligusticum wallichii in Myocardial Infarction Through Network Pharmacology and Experimental Validation

  2025cites this paper
• Intercellular communication after myocardial infarction: macrophage as the centerpiece.

  2025cites this paper
• Macrophage-enriched Sectm1a promotes efficient efferocytosis to attenuate ischemia/reperfusion-induced cardiac injury

  2024cites this paper
• Macrophage metabolic reprogramming: A trigger for cardiac damage in autoimmune diseases.

  2024cites this paper
• The Macrophage–Fibroblast Dipole in the Context of Cardiac Repair and Fibrosis

  2024cites this paper
• Insights into the post-translational modifications in heart failure.

  2024cites this paper
• MFGE8 promotes adult hippocampal neurogenesis in rats following experimental subarachnoid hemorrhage via modifying the integrin β3/Akt signaling pathway

  2024cites this paper
• Macrophages in the infarcted heart acquire a fibrogenic phenotype, expressing matricellular proteins, but do not undergo fibroblast conversion.

  2024cites this paper
• Macrophage‐mediated heart repair and remodeling: A promising therapeutic target for post‐myocardial infarction heart failure

  2024cites this paper
• RNF149 Destabilizes IFNGR1 in Macrophages to Favor Postinfarction Cardiac Repair

  2024cites this paper
• The association between systemic immune-inflammation index and cardiotoxicity related to 5-Fluorouracil in colorectal cancer

  2024cites this paper
• Macrophage heterogeneity in myocardial infarction: Evolution and implications for diverse therapeutic approaches

  2024cites this paper
• Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities

  2024cites this paper
• Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets

  2024cites this paper
• Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities

  2024cites this paper
• The efferocytosis process in aging: Supporting evidence, mechanisms, and therapeutic prospects for age-related diseases

  2024cites this paper
• Novel Perspectives in Chronic Kidney Disease-Specific Cardiovascular Disease

  2024cites this paper
• Global IL4Rα Blockade Exacerbates Heart Failure After an Ischemic Event in Mice and Humans.

  2024cites this paper
• Targeting NPM1 Epigenetically Promotes Postinfarction Cardiac Repair by Reprogramming Reparative Macrophage Metabolism

  2024cites this paper
• Macrophage mediators and mechanisms in cardiovascular disease

  2024cites this paper
• Anti-Inflammatory Neutrophils Reprogram Macrophages toward a Pro-Healing Phenotype with Increased Efferocytosis Capacity

  2024cites this paper
• Genetically Engineered Macrophages Co‐Loaded with CD47 Inhibitors Synergistically Reconstruct Efferocytosis and Improve Cardiac Remodeling Post Myocardial Ischemia Reperfusion Injury

  2024cites this paper
• ATF3 coordinates the survival and proliferation of cardiac macrophages and protects against ischemia–reperfusion injury

  2024cites this paper
• ATF3’s shielding hand to counter ischemia-reperfusion injury in cardiac macrophages

  2024cites this paper
• Protective effects of macrophage-specific integrin α5 in myocardial infarction are associated with accentuated angiogenesis

  2023cites this paper
• MFG-E8 facilitates heart repair through M1/M2 polarization after myocardial infarction by inhibiting CaMKII.

  2023cites this paper
• A+T rich interaction domain protein 3a (Arid3a) impairs Mertk-mediated efferocytosis in cholestasis.

  2023cites this paper
• Macrophage-driven cardiac inflammation and healing: insights from homeostasis and myocardial infarction

  2023cites this paper
• Targeting MFGE8 secreted by cancer-associated fibroblasts blocks angiogenesis and metastasis in esophageal squamous cell carcinoma

  2023cites this paper
• Immune profiling of murine cardiac leukocytes identifies Trem2 as a novel mediator of hypertensive heart failure.

  2023cites this paper
• Cardiac macrophages and emerging roles for their metabolism after myocardial infarction

  2023cites this paper
• SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin

  2023cites this paper
• Novel Therapeutic Avenues for Hypertrophic Cardiomyopathy

  2023cites this paper
• The phagocytic role of macrophage following myocardial infarction

  2023cites this paper
• Immunometabolism at the Heart of Cardiovascular Disease

  2023cites this paper
• The role of macrophage subsets in and around the heart in modulating cardiac homeostasis and pathophysiology

  2023cites this paper
• Macrophages in cardiac remodelling after myocardial infarction

  2023cites this paper
• Defective efferocytosis by aged macrophages promotes STING signaling mediated inflammatory liver injury

  2023cites this paper
• Analysis of the Differentially Expressed Proteins in Donkey Milk in Different Lactation Stages

  2023cites this paper
• How Pyroptosis Contributes to Inflammation and Fibroblast-Macrophage Cross-Talk in Rheumatoid Arthritis

  2022cites this paper
• The Innate Immune System in Cardiovascular Diseases and Its Role in Doxorubicin-Induced Cardiotoxicity

  2022cites this paper
• Scalable Generation of Nanovesicles from Human-Induced Pluripotent Stem Cells for Cardiac Repair

  2022cites this paper
• Emerging Therapeutic Targets for Heart Failure

  2022cites this paper
• Identification of Adipose Tissue as a Reservoir of Macrophages after Acute Myocardial Infarction

  2022cites this paper
• Macrophages in myocardial infarction.

  2022cites this paper
• Mechanisms of efferocytosis in determining inflammation resolution: Therapeutic potential and the association with cardiovascular disease

  2022cites this paper
• Differential effects of Smad2 and Smad3 in regulation of macrophage phenotype and function in the infarcted myocardium.

  2022cites this paper
• The role of endogenous Smad7 in regulating macrophage phenotype following myocardial infarction

  2022cites this paper
• Macrophage efferocytosis with VEGFC and lymphangiogenesis: rescuing the broken heart

  2022cites this paper
• Cardio-omentopexy requires a cardioprotective innate immune response to promote myocardial angiogenesis in mice

  2022cites this paper
• Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation

  2022cites this paper
• Periostin renders cardiomyocytes vulnerable to acute myocardial infarction via pro‐apoptosis

  2022cites this paper
• Macrophage MerTK promotes profibrogenic cross-talk with hepatic stellate cells via soluble mediators

  2022cites this paper
• Resolving the intertwining of inflammation and fibrosis in human heart failure at single-cell level

  2021cites this paper
• Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair

  2021cites this paper
• Novel Mechanisms of Exosome-Mediated Phagocytosis of Dead Cells in Injured Heart

  2021cites this paper
• Therapeutic angiogenesis in coronary artery disease: a review of mechanisms and current approaches

  2021cites this paper
• Innate Lymphoid Cells Promote Recovery of Ventricular Function After Myocardial Infarction

  2021cites this paper
• Water-soluble alkaloids extracted from Aconiti Radix lateralis praeparata protect against chronic heart failure in rats via a calcium signaling pathway.

  2021cites this paper
• Neutrophils in cardiovascular disease: Warmongers, peacemakers or both?

  2021cites this paper
• Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction.

  2021cites this paper
• Cellular Responses to the Efferocytosis of Apoptotic Cells

  2021cites this paper
• Macrophage Metabolic Signaling during Ischemic Injury and Cardiac Repair

  2021cites this paper
• MFGE8 mitigates brain injury in a rat model of SAH by maintaining vascular endothelial integrity via TIGβ5/PI3K/CXCL12 signaling

  2021cites this paper
• Artificial apoptotic cells/VEGF-loaded injectable hydrogel united with immunomodification and revascularization functions to reduce cardiac remodeling after myocardial infarction

  2021cites this paper
• Efferocytosis of vascular cells in cardiovascular disease.

  2021cites this paper
• Macrophage Efferocytosis in Cardiac Pathophysiology and Repair.

  2020cites this paper
• New Approaches to Target Inflammation in Heart Failure: Harnessing Insights from Studies of Immune Cell Diversity.

  2020cites this paper
• MFGE8 attenuates Ang-II-induced atrial fibrosis and vulnerability to atrial fibrillation through inhibition of TGF-β1/Smad2/3 pathway.

  2020cites this paper
• Interleukin-33 Signaling Controls the Development of Iron-Recycling Macrophages

  2020cites this paper
• Efferocytosis during myocardial infarction.

  2020cites this paper
• Macrophage Activities in Myocardial Infarction and Heart Failure

  2020cites this paper
• IL-33 Induces Type-2-Cytokine Phenotype but Exacerbates Cardiac Remodeling Post-Myocardial Infarction with Eosinophil Recruitment, Worsened Systolic Dysfunction, and Ventricular Wall Rupture.

  2020cites this paper
• S100A9 Links Inflammation and Repair in Myocardial Infarction

  2020cites this paper
• Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis

  2020cites this paper
• Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair

  2020cites this paper
• Roles and mechanisms of MFG-E8 in vascular aging-related diseases.

  2020cites this paper
• Emerging roles of neutrophil-borne S100A8/A9 in cardiovascular inflammation.

  2020cites this paper
• Angiogenesis After Acute Myocardial Infarction.

  2020cites this paper
• Post-translational modifications of the ligands: Requirement for TAM receptor activation.

  2020cites this paper
• THE PROTECTIVE ROLE OF PERICARDIAL MACROPHAGES AND THEIR EFFEROCYTOSIS POTENTIAL DURING EXPERIMENTAL CVB3 MYOCARDITIS

  2020cites this paper
• Macrophage Activities inMyocardial Infarction andHeart Failure

  2020cites this paper
• Pro-atherogenic diet accelerates tumor growth in mice through IL-1β and myeloid cell-derived VEGF-A

  2020cites this paper
• Inflammation and fibrosis in murine models of heart failure

  2019cites this paper
• Recombinant Human Milk Fat Globule-Epidermal Growth Factor 8 Attenuates Microthrombosis after Subarachnoid Hemorrhage in Rats.

  2019cites this paper
• Macrophages in Heart Failure with Reduced versus Preserved Ejection Fraction.

  2019cites this paper