Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation
Kristofor E. Glinton, … , Guillermo Oliver, Edward B. Thorp
Kristofor E. Glinton, … , Guillermo Oliver, Edward B. Thorp
Published March 10, 2022
Citation Information: J Clin Invest. 2022;132(9):e140685. https://doi.org/10.1172/JCI140685.
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Research Article Inflammation Vascular biology

Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation

Abstract

Clearance of dying cells by efferocytosis is necessary for cardiac repair after myocardial infarction (MI). Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis after MI. Here, we report that defective efferocytosis by macrophages after experimental MI led to a reduction in cardiac lymphangiogenesis and Vegfc expression. Cell-intrinsic evidence for efferocytic induction of Vegfc was revealed after adding apoptotic cells to cultured primary macrophages, which subsequently triggered Vegfc transcription and VEGFC secretion. Similarly, cardiac macrophages elevated Vegfc expression levels after MI, and mice deficient for myeloid Vegfc exhibited impaired ventricular contractility, adverse tissue remodeling, and reduced lymphangiogenesis. These results were observed in mouse models of permanent coronary occlusion and clinically relevant ischemia and reperfusion. Interestingly, myeloid Vegfc deficiency also led to increases in acute infarct size, prior to the amplitude of the acute cardiac lymphangiogenesis response. RNA-Seq and cardiac flow cytometry revealed that myeloid Vegfc deficiency was also characterized by a defective inflammatory response, and macrophage-produced VEGFC was directly effective at suppressing proinflammatory macrophage activation. Taken together, our findings indicate that cardiac macrophages promote healing through the promotion of myocardial lymphangiogenesis and the suppression of inflammatory cytokines.

Authors

Kristofor E. Glinton, Wanshu Ma, Connor Lantz, Lubov S. Grigoryeva, Matthew DeBerge, Xiaolei Liu, Maria Febbraio, Mark Kahn, Guillermo Oliver, Edward B. Thorp

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Figure 6

Myeloid Vegfc overexpression leads to improved cardiac function and increased lymphangiogenesis after MI.

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Myeloid Vegfc overexpression leads to improved cardiac function and incr...
(A) VegfcGOF LysMCre mice and littermate controls were subjected to permanent ligation of the LAD artery. Parasternal short-axis M-mode measurements were collected prior to surgery (day 0) and again on day 21 after the ligation procedure to obtain EF measurements as an indicator of cardiac function. (B) Additional indices measured by echocardiography showed significantly improved indicators of systolic function including ventricular wall thickness, internal diameter, and volume. n = 9 control mice and n = 5 VegfcGOF LysMCre mice. (C) Representative photomicrographs and quantification of imaging from cardiac sections that were immunostained for LYVE1 in VegfcGOF LysMCre mice versus control, after MI. n = 4 per group. Original magnification, ×10. (D) Cardiac macrophages were assessed by flow cytometric analysis 7 days after MI. No significant differences in the absolute number of macrophages were observed. However, VegfcGOF LysMCre mice maintained a higher frequency of reparative MHCIIlo macrophages. *P < 0.05 and **P < 0.01, by 2-tailed, unpaired t test (A–D).