Lymphatic Endothelial C-C Motif Chemokine Ligand 2 Enhances Lymphangiogenesis and Lymphatic Clearance of Macrophages Following Myocardial Infarction.

Abstract

BACKGROUND: Inflammatory responses are crucial in the pathological cardiac remodeling and tissue repair after myocardial infarction (MI). The lymphatic endothelial cells (LECs) significantly influence immune cell clearance and mitigate cardiac inflammation. Chemokines are known to tightly regulate immune cell mobilization within the infarcted heart, affecting both inflammation and remodeling. However, the role of chemokines expressed by LECs in the regulation of cardiac inflammation post MI remains unclear. Our study aimed to investigate whether LEC-expressing CCL2 (C-C motif chemokine ligand 2) regulated post-MI cardiac remodeling and its underlying molecular mechanisms. METHODS: We generated LEC-conditionalknockout mice and induced acute MI via left anterior descending coronary artery ligation in these mice. Cardiac function was assessed by echocardiography, and post-MI remodeling was evaluated through serial histological analysis. Immunostaining was performed to examine lymphangiogenesis, macrophage infiltration, and macrophage clearance in the myocardium. Additionally, in vitro assays were conducted to investigate the role of LEC-derived CCL2 in macrophage chemotaxis and lymphangiogenesis, including analyses of AKT/ETS1 (E26 oncogene homolog 1) signaling activation and VEGFC (vascular endothelial growth factor C) expression. RESULTS: Our results showed that the LEC-deficiency exacerbated cardiac dysfunction and worsened adverse cardiac remodeling after MI. Further immunostaining analysis showed that the loss of CCL2 in LECs impeded post-MI lymphangiogenesis and increased macrophage infiltration in post-MI myocardium and impaired macrophage clearance via afferent cardiac lymphatics. This led to exacerbated inflammatory responses and pathological cardiac remodeling after MI. In vitro studies identified that LEC-derived CCL2 not only induced chemotaxis of macrophages but also activated AKT/ETS1 signaling, enhancing VEGFC expression and promoting lymphangiogenesis. CONCLUSIONS: This study reveals that cardiac LEC-expressing CCL2 tightly controls macrophage trafficking via lymphatic vessels in injured hearts and thus diminishes post-MI inflammatory responses and lessens adverse cardiac remodeling. Our findings suggest that modulating CCL2 signaling in LECs could provide a promising therapeutic target for resolving excessive inflammation and ameliorating adverse cardiac remodeling after MI.