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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.
Arteriosclerosis, Thrombosis, and Vascular Biology
|March 27, 2025
Summary
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.
