Lymphatic Activation of ACKR3 Signaling Regulates Lymphatic Response After Ischemic Heart Injury

BACKGROUND: Ischemic heart disease is a prevalent cause of death and disability worldwide. Recent studies reported a rapid expansion of the cardiac lymphatic network upon ischemic heart injury and proposed that cardiac lymphatics may attenuate tissue edema and inflammatory mechanisms after ischemic heart injury. Nevertheless, the mechanisms through which hypoxic conditions affect cardiac lymphangiogenesis and function remain unclear. Here, we aimed to characterize the role of the AM (adrenomedullin) decoy receptor ACKR3 (atypical chemokine receptor-3) in the lymphatic response following ischemic heart injury. METHODS: Spatial assessment of ACKR3 signaling in the heart after ischemic heart injury was conducted using ACKR3-Tango-GFP reporter mice. Roles of ACKR3 after ischemic heart injury were characterized in Ackr3 ∆Lyve1 mice and in cultured human lymphatic endothelial cells exposed to hypoxia. RESULTS: Using the novel ACKR3-Tango-GFP reporter mice, we detected activation of ACKR3 signaling in cardiac lymphatics adjacent to the site of ischemic injury of left anterior descending artery ligation. Ackr3 ∆Lyve1 mice exhibited better survival after left anterior descending artery ligation, especially within the first couple of days post-injury, and were protected from the formation of acute tissue edema. Ackr3 ∆Lyve1 mice exhibited a denser cardiac lymphatic network after left anterior descending artery ligation, especially in the injured tissues. Transcriptomic analysis revealed changes in cardiac lymphatic gene expression patterns that have been associated with extracellular matrix remodeling and immune activation. We also found that ACKR3 plays a critical role in regulating continuous cell-cell junction dynamics in lymphatic endothelial cells under hypoxic conditions. CONCLUSIONS: Lymphatic expression of ACKR3 governs numerous processes following ischemic heart injury, including the lymphangiogenic response, edema protection, and overall survival. These results expand our understanding of how the heart failure biomarker AM, regulated by lymphatic ACKR3, may exert its roles after ischemic cardiac injury.