Abstract 1027: Role of Lymphangiogenesis in Myocardial Infarction
Background Recent reports have emphasized the important role of inflammation in the pathophysiology of cardiovascular diseases. Lymphatic system is important in immune responses. The vascular endothelial growth factor (VEGF)-C/VEGF-D/VEGF receptor (VEGFR)-3 signaling pathway is crucial for lymphangiogenesis. However, the roles of lymphatic vessels in myocardium remain unclear. This study was designed to examine the role of myocardial lymphangiogenesis in a murine model of myocardial infarction.
Methods and Results Eight-week-old C57BL/6 mice underwent coronary artery ligation (day 0). The hearts were fixed in 10% formalin, embedded in paraffin, sectioned, and analysed, performing immunohistochemical staining on day 1, 3, 4, 5, 7, 9, 12, 14, 28, 56, 112, and 140. We used the antibodies against VEGFR-3 or podopranin which is specific for lymphatic vessels. In addition, we examined the effects of VEGF-C156S, lymphangiogenesis inducer, or VEGFR3-Fc, lymphangiogenesis blocker, on infarct size and hemodynamics in the same model, using adenoviruses gene transfer. Immunohistochemical staining for VEGFR-3 and podopranin resulted in successful labeling of lymphatic capillaries in myocardium. Lymphatic vessels appeared in the infarcted myocardium 3 days after coronary artery ligation. Lymphatic vessels were enlarged in the subacute phase. In the chronic phase, lymphatic vessels were distributed in the infarcted myocardium, right ventricle, and pericardium. Lymphatic density and area increased from day 3 to chronic phase. The number of lymphatic vessels was about sixteen times (94 ± 6.8 on day 140 vs. 5.8 ± 0.6 vessels/mm2 on day3, p<0.05) and lymphatic area was eighteen times (7.3 ± 0.9 on day 140 vs. 0.4 ± 0.2 % on day3, p<0.05) than those on day 3. VEGF-C156S and VEGFR3-Fc proteins were successfully expressed in myocardium. VEGF-C156S improved left ventricular remodeling and hemodynamic parameters. We also detected lymphatic capillaries by immunohistochemistry in human hearts of patients with myocardial infarction.
Conclusions These findings provide new insights into the role of myocardial lymphangiogenesis in the pathophysiology of myocardial infarction, and suggest therapeutic benefits by modulating lymphangiogenesis in this disease.