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VEGF-C-mediated cardiac lymphangiogenesis promotes inflammation resolution in autoimmune acute myocarditis in mice

Nakanishi, Nanako ; Hara, Shigeru ; Nagaharu, Keiki LU orcid ; Matsuyama, Ryo ; Fujita, Soyoka ; Nakamori, Shiro ; Okamoto, Ryuji ; Dohi, Kaoru ; Hiroe, Michiaki and Imanaka-Yoshida, Kyoko , et al. (2026) In Cardiovascular Research 122(6). p.707-722
Abstract

Aims: Acute myocarditis is an immune-mediated inflammatory disease characterized by myocardial inflammation and oedema. Although cardiac lymphatic vessels are essential for fluid clearance and immune regulation, their role in modulating autoimmune cardiac inflammation remains largely undefined. We aimed to determine whether promoting lymphangiogenesis could mitigate inflammation and preserve cardiac function in autoimmune myocarditis. Methods and results: We used a murine model of experimental autoimmune myocarditis (EAM) induced by cardiac myosin peptide immunization and examined human autopsy hearts for lymphatic expansion. Mice received VEGF-C C156S, a VEGFR3-selective agonist, starting one week after immunization. We assessed... (More)

Aims: Acute myocarditis is an immune-mediated inflammatory disease characterized by myocardial inflammation and oedema. Although cardiac lymphatic vessels are essential for fluid clearance and immune regulation, their role in modulating autoimmune cardiac inflammation remains largely undefined. We aimed to determine whether promoting lymphangiogenesis could mitigate inflammation and preserve cardiac function in autoimmune myocarditis. Methods and results: We used a murine model of experimental autoimmune myocarditis (EAM) induced by cardiac myosin peptide immunization and examined human autopsy hearts for lymphatic expansion. Mice received VEGF-C C156S, a VEGFR3-selective agonist, starting one week after immunization. We assessed lymphangiogenesis, oedema, immune infiltration, fibrosis, and cardiac function using immunohistochemistry, echocardiography, qPCR, and RNA sequencing. VEGF-C treatment enhanced lymphatic sprouting and function, reduced myocardial water content, and attenuated immune cell infiltration and interstitial fibrosis. Cardiac function was preserved, as measured by echocardiography. Notably, VEGF-C selectively decreased the accumulation of iNOS+ inflammatory macrophages without broadly suppressing T cells or reparative macrophage subsets. Transcriptomic profiling confirmed down-regulation of inflammatory gene programmes associated with macrophage activation. Conclusion: Early stimulation of cardiac lymphangiogenesis by VEGF-C promotes inflammation resolution, limits myocardial injury, and preserves cardiac function in autoimmune myocarditis. Targeting the cardiac lymphatic system may represent a novel therapeutic strategy for inflammatory heart disease.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cardiac fibrosis, Cardiac lymphatic vessels, Macrophage, Myocarditis, Vascular endothelial growth factor C
in
Cardiovascular Research
volume
122
issue
6
pages
16 pages
publisher
Oxford University Press
external identifiers
  • scopus:105037127799
  • pmid:41843753
ISSN
0008-6363
DOI
10.1093/cvr/cvag057
language
English
LU publication?
yes
id
7a02bdce-74ae-41aa-be5a-5285845fd564
date added to LUP
2026-05-29 14:37:31
date last changed
2026-05-30 03:29:10
@article{7a02bdce-74ae-41aa-be5a-5285845fd564,
  abstract     = {{<p>Aims: Acute myocarditis is an immune-mediated inflammatory disease characterized by myocardial inflammation and oedema. Although cardiac lymphatic vessels are essential for fluid clearance and immune regulation, their role in modulating autoimmune cardiac inflammation remains largely undefined. We aimed to determine whether promoting lymphangiogenesis could mitigate inflammation and preserve cardiac function in autoimmune myocarditis. Methods and results: We used a murine model of experimental autoimmune myocarditis (EAM) induced by cardiac myosin peptide immunization and examined human autopsy hearts for lymphatic expansion. Mice received VEGF-C C156S, a VEGFR3-selective agonist, starting one week after immunization. We assessed lymphangiogenesis, oedema, immune infiltration, fibrosis, and cardiac function using immunohistochemistry, echocardiography, qPCR, and RNA sequencing. VEGF-C treatment enhanced lymphatic sprouting and function, reduced myocardial water content, and attenuated immune cell infiltration and interstitial fibrosis. Cardiac function was preserved, as measured by echocardiography. Notably, VEGF-C selectively decreased the accumulation of iNOS<sup>+</sup> inflammatory macrophages without broadly suppressing T cells or reparative macrophage subsets. Transcriptomic profiling confirmed down-regulation of inflammatory gene programmes associated with macrophage activation. Conclusion: Early stimulation of cardiac lymphangiogenesis by VEGF-C promotes inflammation resolution, limits myocardial injury, and preserves cardiac function in autoimmune myocarditis. Targeting the cardiac lymphatic system may represent a novel therapeutic strategy for inflammatory heart disease.</p>}},
  author       = {{Nakanishi, Nanako and Hara, Shigeru and Nagaharu, Keiki and Matsuyama, Ryo and Fujita, Soyoka and Nakamori, Shiro and Okamoto, Ryuji and Dohi, Kaoru and Hiroe, Michiaki and Imanaka-Yoshida, Kyoko and Maruyama, Kazuaki}},
  issn         = {{0008-6363}},
  keywords     = {{Cardiac fibrosis; Cardiac lymphatic vessels; Macrophage; Myocarditis; Vascular endothelial growth factor C}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{707--722}},
  publisher    = {{Oxford University Press}},
  series       = {{Cardiovascular Research}},
  title        = {{VEGF-C-mediated cardiac lymphangiogenesis promotes inflammation resolution in autoimmune acute myocarditis in mice}},
  url          = {{http://dx.doi.org/10.1093/cvr/cvag057}},
  doi          = {{10.1093/cvr/cvag057}},
  volume       = {{122}},
  year         = {{2026}},
}