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 post MI. Here we report that defective efferocytosis by macrophages after experimental MI leads 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 sequencing and cardiac flow cytometry revealed that myeloid Vegfc deficiency was also characterized by a defective inflammatory response, and macrophages-produced VEGFC was directly effective at suppressing pro-inflammatory macrophage activation. Taken together, our findings indicate that cardiac macrophages promote healing through the promotion of myocardial lymphangiogenesis and the suppression of inflammatory cytokines.

The role of Vegfc signaling during cardiac regeneration in zebrafish

“…In line with my findings that vegfc is expressed in cECs during cardiac regeneration in zebrafish, a previous study revealed that Vegfc is expressed in ECs in neonatal mice after cardiac injury, further confirming that Vegfc acts as an angiocrine following cardiac injury in regenerative settings (Quaife-Ryan et al, 2017). On the other hand, it has been very recently reported that macrophages are a source of VEGFC following cardiac injury in adult mice (Glinton et al, 2022). It would be interesting to investigate if VEGFC from different cellular sources contribute to a pleiotropic role to promote cardiac regeneration following injury.…”

Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation

“…In further support of a role of monocytes/macrophages in promoting LM progression, we found that the blockade of their recruitment or differentiation using anti-CSF1R or anti-CCL2/MCP1 antibodies inhibited Pik3ca -driven lymphatic overgrowth. Although our study did not assess a causal link between macrophage recruitment, VEGF-C production, and lymphangiogenesis in a wild-type setting, previous studies in different disease contexts have established such links ( Schoppmann et al, 2002 ; Alishekevitz et al, 2016 ; Glinton et al, 2022 ; Kataru et al, 2009 ). Of note, the recruited macrophages may additionally produce factors that promote proteolytic processing of, or synergize with VEGF-C, to enhance its lymphangiogenic activity ( Jha et al, 2017 ).…”

KRAS mutant–driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer

“…It has been proposed that VEGF-C represents the core regulator for inducing tumor lymphangiogenesis ( 32 ). Accordingly, we analyzed whether hnRNPA1 participates in regulating VEGF-C to promote the lymphangiogenesis of PDAC.…”