Backgrounds: The lymphangiogenesis after myocardial infarction (MI) has not previously been examined. We investigated whether bone marrow (BM)-derived endothelial progenitor cells (EPC) contribute in lymphatic distribution in the myocardial remodeling after MI.
Methods and Results: We made mice (C57bl/6J) MI by ligation of the left anterior descending coronary artery and treated with PBS or EPC. Real-time RT-PCR with 2/4 week myocardial tissue samples revealed lymphangiogenetic cytokines expressed significantly higher level of VEGF C (8.5 fold, p < 0.05), VEGF D (6.1 fold, p < 0.05), Lyve-1 (15 fold, p < 0.05), Prox-1 (11 fold, p < 0.05) in the PBS group compared to the EPC group. Newly formed lymphatic vessels could be found in the peri-infarction area. The PBS group showed significant higher density of lymphatic vessels compared to the EPC group. Echocardiography showed that from 2 wk after treatment, left ventricle (LV) dimensions at both systole and diastole were significantly smaller in the EPC group than in the PBS group (p < 0.01) and LV fractional shortening was better in the EPC group accordingly(p < 0.01). These findings suggest that EPC transplantation decreases lymphangiogenesis and adverse ventricular remodeling within 2 wk after MI. To trace the BM-derived cells, we performed BM transplantation (BMT) with GFP reporter cells. We made MI in BMT mice at least 4 weeks later BMT and counted GFP positive cells incorporated into lymphatic vessels in the myocardium. We also performed immunohistochemistry to identify the fate of the incorporated cells. GFP positive BM-derived cells contribute to newly formed lymphatics.
Conclusions: Lymphangiogenic markers increased in a mouse model of MI. EPC transplantation decreases lymphangiogenesis and adverse ventricular remodeling after MI. EPC contribute to newly formed lymphatic vessels in peri-infarction area. These novel findings suggest that new lymphatic vessels may be formed in severely damaged myocardium and involved in unfavorable myocardial remodeling after MI.