The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction
Joaquim Miguel Vieira, … , David G. Jackson, Paul R. Riley
Joaquim Miguel Vieira, … , David G. Jackson, Paul R. Riley
Published July 9, 2018
Citation Information: J Clin Invest. 2018;128(8):3402-3412. https://doi.org/10.1172/JCI97192.
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Research Article Inflammation Vascular biology

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.

Authors

Joaquim Miguel Vieira, Sophie Norman, Cristina Villa del Campo, Thomas J. Cahill, Damien N. Barnette, Mala Gunadasa-Rohling, Louise A. Johnson, David R. Greaves, Carolyn A. Carr, David G. Jackson, Paul R. Riley

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Figure 7

Disruption of LYVE-1–dependent clearance of immune cells by lymphatics is detrimental to cardiac function after injury.

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Disruption of LYVE-1–dependent clearance of immune cells by lymphatics i...
(A–C) Longitudinal cine MRI analyses of infarcted control and Lyve1–/– hearts on days 7 and 21 after injury showing reduced EF (A), SV (B), and ESV (C) in mutants, compared with controls. Data are presented as mean ± SEM; control, n = 10 hearts; Lyve1–/– , n = 10 hearts. Significant differences were calculated using 2-way ANOVA with repeated measures (*P ≤ 0.05, **P ≤ 0.01). (D–G) Representative 1-mm-thick mid-ventricular short-axis cine MRI frames for control (D and E) and Lyve1–/– (F and G) hearts in diastole (D and F) and systole (E and G) on day 21 after MI. (H–N) Histological characterization of control and Lyve1–/– hearts on day 21 after MI using Masson’s trichrome (H and I) and Picrosirius red staining (J–N), documenting excessive collagen deposition/fibrotic scarring (blue in H and I; red in J and K; yellow-orange birefringence in L and M) in mutant hearts. Note that Picrosirius staining was visualized under brightfield (J and K) and polarized light (L and M), leading to birefringence of the collagen fibers, to further characterize the type of fibers making up the scar, i.e. type I (thicker; yellow-orange) or type III (thin; green). (N) Quantification of fibrotic scarring as (Picrosirius) yellow-orange birefringence signal/area ratio. Data are presented as mean ± SEM; control, n = 5 hearts; Lyve1–/–, n = 5 hearts. Significant differences were calculated using an unpaired, 2-tailed Student’s t test (*P ≤ 0.05). Scale bars: 1 mm; except D and F, 2 mm.