The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction

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.

Application of microscale culture technologies for studying lymphatic vessel biology

“…For instance, it was shown that stimulating cardiac lymphangiogenesis in vivo with VEGF-C improves immune cell clearance and the resolution of inflammation following MI. 114 Similarly, kidney-specific expression of VEGF-D increased renal lymphangiogenesis, reduced renal immune cell accumulation, and prevented hypertension. 115 Furthermore, lymphangiogenesis is required to mitigate impaired wound healing which is a common complication in diabetic patients.…”

“…Moreover, recent studies using conditional mouse models have provided novel insights on the therapeutic implications of enhancing lymphatic vessel growth. For instance, it was shown that stimulating cardiac lymphangiogenesis in vivo with VEGF‐C improves immune cell clearance and the resolution of inflammation following MI . Similarly, kidney‐specific expression of VEGF‐D increased renal lymphangiogenesis, reduced renal immune cell accumulation, and prevented hypertension .…”

Myocardial Infarction: Perspectives on Cardiac Regeneration and Cardiac Remote Conditioning Interventions to Limit Cellular Injury

“…Furthermore, exogenous application of CXCL12 (chemotactic ligand induced by hypoxia) on the epicardium induces formation of collateral vessels by migration of arterial endothelial cells along pre-existing capillaries (arterial re-assembly) [66] [67]. An additional element of cardiac repair that is the formation of lymph vessels within the ischemic region; stimulation of lymphangiogenesis after infarction is necessary for removal of inflammatory cells and cellular by-products from the zone under repair [68]. Impeding formation of lymph vessels limits immune cell clearance and worsens clinical outcomes.…”

Repair, regenerate and reconstruct: meeting the state-of-the-art

“…He showed that VEGFC, a growth factor involved in coronary vessel development, induces lymphatic vasculature near to the infarction zone. These new lymphatic vessels function to traffic immune cells, a process dependent upon the LYVE1 receptor, which when mutated results in cardiac deterioration (Vieira et al, 2018).…”