Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction

Area of Science:

• Cardiovascular Biology
• Immunology
• Regenerative Medicine

Background:

• Lymphatics are crucial for fluid and immune cell clearance.
• Cardiac lymphangiogenesis is a potential therapeutic target for heart failure post-myocardial infarction (MI).
• Immune cells can influence lymphatic function and cardiac remodeling.

Purpose of the Study:

• To investigate gene therapy's effects on cardiac lymphangiogenesis post-MI in rodents.
• To determine the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart.

Main Methods:

• Adenoviral versus adeno-associated viral gene delivery of VEGF-C_C156S in mice.
• Inhibition of VEGF-C/-D signaling using adeno-associated viral delivery of soluble VEGFR3.
• Pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice.

Main Results:

• Sustained VEGF-C_C156S therapy via AAV increased cardiac lymphangiogenesis, reducing inflammation and dysfunction post-MI.
• VEGF-C/-D inhibition limited infarct lymphangiogenesis but improved cardiac function by suppressing T-cell infiltration.
• CD4+ and CD8+ T cells were found to suppress cardiac lymphangiogenesis post-MI, partly via interferon-γ.

Conclusions:

• Therapeutic lymphangiogenesis using AAV-VEGF-C_C156S can accelerate cardiac inflammation resolution post-MI.
• Cardiac-recruited T cells negatively impact lymphatic remodeling after MI.
• This study reveals a critical interconnection between immune cells and lymphatics in cardiac repair post-injury.