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Updated: May 20, 2025
A Murine Model of Myocardial Ischemia-reperfusion Injury through Ligation of the Left Anterior Descending Artery
Published on: April 10, 2014
Lymphatic Activation of ACKR3 Signaling Regulates Lymphatic Response After Ischemic Heart Injury
Laszlo Balint1, Shubhangi Patel1, Donald Stephen Serafin1
1Department of Cell Biology and Physiology (L.B., S.P., D.S.S., H.Z., K.E.Q., A.A., B.M.K., K.M.C.), University of North Carolina at Chapel Hill.
Insights
The atypical chemokine receptor-3 (ACKR3) decoy receptor is crucial for cardiac lymphatic function after ischemic heart injury. Blocking ACKR3 improves survival and reduces edema by enhancing the cardiac lymphatic network.
Area of Science:
- Cardiovascular Biology
- Lymphatic System Research
- Molecular Medicine
Background:
- Ischemic heart disease is a leading global cause of mortality.
- Cardiac lymphatics expand after injury, potentially reducing edema and inflammation.
- Mechanisms linking hypoxia to cardiac lymphangiogenesis remain unclear.
Purpose of the Study:
- To investigate the role of the AM (adrenomedullin) decoy receptor ACKR3 (atypical chemokine receptor-3) in the cardiac lymphatic response to ischemic injury.
Main Methods:
- Utilized ACKR3-Tango-GFP reporter mice for spatial assessment of ACKR3 signaling.
- Studied ACKR3 function in Ackr3 knockout mice and human lymphatic endothelial cells under hypoxia.
Main Results:
- ACKR3 signaling activated in cardiac lymphatics post-ischemic injury.
- Ackr3 knockout mice showed improved survival, reduced edema, and a denser lymphatic network.
- ACKR3 regulates lymphatic endothelial cell junctions under hypoxia and impacts gene expression related to matrix remodeling and immune activation.
Conclusions:
- Lymphatic ACKR3 is vital for lymphangiogenesis, edema protection, and survival after ischemic heart injury.
- Findings clarify the role of AM, regulated by ACKR3, in cardiac injury response.
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 (green fluorescent protein) 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.
