The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction

Myocardial infarction (MI) arising from obstruction of the coronary circulation engenders massive cardiomyocyte loss which is replaced 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 the recombinant vascular endothelial growth factor C (VEGF-C) improves clearance of the acute inflammatory response post-MI, by trafficking immune cells to draining mediastinal lymph nodes (MLNs), in a process dependent on the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Deletion of Lyve1, 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 validate targeting of the lymphatic-immune cell axis as a novel therapeutic paradigm to promote immune modulation and heart repair