Abstract
Myocardial infarction (MI) arising from obstruction of the coronary circulation engenders massive cardiomyocyte loss and replacement by non-contractile scar tissue, leading to pathological remodeling, dysfunction, and ultimately heart failure. This is presently a global health problem for which there is no effective cure. Following MI, the innate immune system directs the phagocytosis of dead cell debris in an effort to stimulate cell repopulation and tissue renewal. In the mammalian adult heart, however, the persistent influx of immune cells, coupled with the lack of an inherent regenerative capacity, results in cardiac fibrosis. Here, we reveal that stimulation of cardiac lymphangiogenesis with VEGF-C improves clearance of the acute inflammatory response after MI by trafficking immune cells to draining mediastinal lymph nodes (MLNs) in a process dependent on lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Deletion of Lyve1 in mice, preventing docking and transit of leukocytes through the lymphatic endothelium, results in exacerbation of chronic inflammation and long-term deterioration of cardiac function. Our findings support targeting of the lymphatic/immune cell axis as a therapeutic paradigm to promote immune modulation and heart repair.
Highlights
The lymphatic system is a network of vessels that pervades the entire body, complementary to the blood cardiocirculatory system
Lymphangiogenesis, begins early during embryogenesis and is promoted by VEGF-C and VEGF-D signaling through their cognate receptor, VEGFR-3, which is expressed in both blood and lymphatic endothelium and becomes specified to the latter toward the end of development
The epicardium is a site of VEGF-C expression [20], and in dermal wounding studies CD11b+ macrophages act as a source of VEGF-C and VEGF-D in response to inflammatory stimuli [5]
Summary
The lymphatic system is a network of vessels that pervades the entire body, complementary to the blood cardiocirculatory system It comprises blind-ended capillaries that collect extravasated interstitial fluid, macromolecules, and leukocytes from the periphery of the body, preventing their accumulation in tissues, and transports them via lymph through larger collecting afferent vessels toward draining lymph nodes [1]. These are secondary lymphoid organs, enriched for naive lymphocytes, that filter the lymph to detect foreign particles (antigens), triggering lymphocyte activation and an adaptive immune response [1, 2]. Lymphangiogenesis, begins early during embryogenesis and is promoted by VEGF-C and VEGF-D signaling through their cognate receptor, VEGFR-3, which is expressed in both blood and lymphatic endothelium and becomes specified to the latter toward the end of development
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