Rationale It is now recognized that macrophages residing within developing and adult tissues are derived from diverse progenitors including those of embryonic origin. Although the functions of macrophages in adult organisms are well studied, the functions of macrophages during organ development remain largely undefined. Moreover, it is unclear whether distinct macrophage lineages have differing functions. Objective To address these issues, we investigated the functions of macrophage subsets resident within the developing heart, an organ replete with embryonic-derived macrophages. Methods and Results Using a combination of flow cytometry, immunostaining, and genetic lineage tracing, we demonstrate that the developing heart contains a complex array of embryonic macrophage subsets that can be divided into chemokine (C-C motif) receptor 2− and chemokine (C-C motif) receptor 2+ macrophages derived from primitive yolk sac, recombination activating gene 1+ lymphomyeloid, and Fms-like tyrosine kinase 3+ fetal monocyte lineages. Functionally, yolk sac–derived chemokine (C-C motif) receptor 2− macrophages are instrumental in coronary development where they are required for remodeling of the primitive coronary plexus. Mechanistically, chemokine (C-C motif) receptor 2− macrophages are recruited to coronary blood vessels at the onset of coronary perfusion where they mediate coronary plexus remodeling through selective expansion of perfused vasculature. We further demonstrate that insulin like growth factor signaling may mediate the proangiogenic properties of embryonic-derived macrophages. Conclusions Together, these findings demonstrate that the embryonic heart contains distinct lineages of embryonic macrophages with unique functions and reveal a novel mechanism that governs coronary development.

R e s e a R c h a R t i c l e5 1Ketogenic insufficiency causes hepatic inflammation, injury, and altered glucose metabolism in the setting of carbohydrate-replete overnutrition. To determine the effects of ketogenic insufficiency in the context of overnutrition, mice previously receiving ASOs for 2 weeks while on a standard low-fat chow diet were then maintained for 8 weeks on a 60% high-fat diet (HFD) commonly used to induce hyperglycemia, hepatic steatosis, and inflammation in WT mice. HMGCS2 immunoblots indicated that hepatic HMGCS2 mice (Supplemental Figure 2, A-C). HMGCS2 ASO-treated mice also exhibited normal serum free fatty acid (FFA) and TAG concentrations and a normal physiologic distribution of residual βOHB and AcAc (Supplemental Figure 2, D-F). Interestingly, HMGCS2 ASO-treated mice displayed mild, but very consistently elevated, blood glucose concentrations (160.9 ± 3.2 mg/dl vs. 145.0 ± 3.4 mg/dl in controls, n = 28-36/group, P = 0.0013), without changes in serum insulin concentrations (Supplemental Figure 2, G and H). C]pyruvate, quantified by NMR profiling of perfused liver extracts from ASO-treated mice fed a 60% HFD for 8 weeks. n = 4-5/group. *P < 0.05, **P < 0.01, ***P < 0.001 by Student's t test.

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SummaryCardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2−) macrophages. Herein, we identify an essential role for CCR2− macrophages in the chronically failing heart. Depletion of CCR2− macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2− macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4) dependent pathway that controlled growth factor expression. These findings establish a role for tissue resident macrophages in adaptive cardiac remodeling and introduce a new mechanism of cardiac macrophage activation.