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

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Houssari , M , Dumesnil , A , Tardif , V , Kivela , R , Pizzinat , N , Boukhalfa , I , Godefroy , D , Schapman , D , Hemanthakumar , K A , Bizou , M , Henry , J-P , Renet , S , Riou , G , Rondeaux , J , Anouar , Y , Adriouch , S , Fraineau , S , Alitalo , K , Richard , V , Mulder , P & Brakenhielm , E 2020 , ' Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction ' , Arteriosclerosis, Thrombosis, and Vascular Biology , vol. 40 , no. 7 , pp. 1722-1737 . https://doi.org/10.1161/ATVBAHA.120.314370

Title: Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction
Author: Houssari, Mahmoud; Dumesnil, Anais; Tardif, Virginie; Kivela, Riikka; Pizzinat, Nathalie; Boukhalfa, Ines; Godefroy, David; Schapman, Damien; Hemanthakumar, Karthik A.; Bizou, Mathilde; Henry, Jean-Paul; Renet, Sylvanie; Riou, Gaetan; Rondeaux, Julie; Anouar, Youssef; Adriouch, Sahil; Fraineau, Sylvain; Alitalo, Kari; Richard, Vincent; Mulder, Paul; Brakenhielm, Ebba
Contributor: University of Helsinki, Kivelä Lab
University of Helsinki, HUSLAB
Date: 2020-07
Language: eng
Number of pages: 16
Belongs to series: Arteriosclerosis, Thrombosis, and Vascular Biology
ISSN: 1079-5642
URI: http://hdl.handle.net/10138/318487
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)-C(C156S)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-gamma, 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-C-C156S. 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.
Subject: heart failure
inflammation
interferon
lymphangiogenesis
macrophages
T-CELLS
DENDRITIC CELLS
VEGF-C
INFLAMMATORY RESPONSE
LYMPHANGIOGENESIS
ACTIVATION
STIMULATION
VESSELS
REPAIR
3121 General medicine, internal medicine and other clinical medicine
3111 Biomedicine
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