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

Abstract

OBJECTIVE:

Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart. Approach and Results: Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-CC156S therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4+ and CD8+ T cells potently suppress, in part through interferon-γ, cardiac lymphangiogenesis post-MI.

CONCLUSIONS:

We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-CC156S. Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury.

• Authors: Mahmoud Houssari, Anais Dumesnil, Virginie Tardif, Riikka Kivelä, Nathalie Pizzinat, Ines Boukhalfa, David Godefroy, Damien Schapman, Karthik A Hemanthakumar, Mathilde Bizou, Jean-Paul Henry, Sylvanie Renet, Gaetan Riou, Julie Rondeaux, Youssef Anouar, Sahil Adriouch, Sylvain Fraineau, Kari Alitalo, Vincent Richard, Paul Mulder, Ebba Brakenhielm
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 40 Issue 7 Pg. 1722-1737 (07 2020) ISSN: 1524-4636 [Electronic] United States
• PMID: 32404007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IFNG protein, mouse
• VEGFC protein, human
• Vascular Endothelial Growth Factor C
• Interferon-gamma
• FLT4 protein, human
• Vascular Endothelial Growth Factor Receptor-3

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Dependovirus (genetics)
• Disease Models, Animal
• Female
• Genetic Therapy
• Genetic Vectors
• Interferon-gamma (metabolism)
• Lymphangiogenesis
• Lymphatic Vessels (immunology, metabolism, physiopathology)
• Male
• Mice, Inbred C57BL
• Myocardial Infarction (genetics, immunology, metabolism, therapy)
• Myocardium (immunology, metabolism, pathology)
• Rats, Wistar
• Recovery of Function
• Signal Transduction
• Time Factors
• Vascular Endothelial Growth Factor C (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-3 (genetics, metabolism)
• Ventricular Function, Left