Daniel Jenkins

 Introduction. Acute myocardial infarction (MI) is one of the leading causes of morbidity and mortality in the western world.¹ It is estimated that over 750,000 people in the United States suffer from MI each year.² Acute MI is caused by a loss of blood flow to a region of the heart, resulting in local tissue necrosis and cell death.³ Acute inflammation and a fibrotic injury response occurs followed by chronic inflammation and fibrosis that can spread to surrounding healthy tissue.⁴ The chronic inflammation is associated with a prolonged increase in macrophage accumulation following an MI.⁵ Lymphatic vessels aid in immune cell trafficking and are critical following cardiac injury.⁶ Vascular endothelial growth factor C (VEGF-C) acts through VEGFR-3 to stimulate cardiac lymphangiogenesis, and previous studies have shown that VEGF-C therapy enhances post-MI lymphangiogenesis.⁷ Therefore, VEGF-C could represent a therapeutic strategy post-MI as a means to reduce macrophage levels and fibrosis. Methods. To induce MI, mice underwent ligation of left anterior descending coronary artery. VEGF-C_C152S intraperitoneal injections or direct left ventricle injections of VEGF-C_C152S-loaded albumin-alginate microparticles were utilized to induce therapeutic lymphangiogenesis. Augmented lymphangiogenesis was detected using whole mount X-gal staining for VEGFR-3^LacZ/+. Ejection fraction measurements were made by echocardiography to assess cardiac function. Immunohistochemistry staining for CD68+ macrophages in the left ventricle and mediastinal lymph nodes were used to quantify macrophage levels. Collagen density was calculated by measuring areas of Sirius Red staining in viable left ventricle cryosections. Results. VEGF-C_C152S treatment groups showed an increased area of lymphangiogenesis at 7 days post MI, and significantly reduced end systolic volumes with improved ejection fractions at 14 and 21 days post-MI compared to sham groups.⁷ VEGF-C_C152S treatment groups showed a significant dose dependent reduction in macrophages in both infarcted and non-infarcted tissue at 3 weeks post-MI.⁴ Significantly increased macrophage levels were identified in mediastinal lymph nodes in VEGF-C_C152S treatment groups vs. intact and control groups 7 days post-MI.⁸ VEGF-C_C152S treatment groups showed a significant decrease in fibrosis of left ventricle in non-infarcted tissue 8 weeks post-MI.⁴ Conclusions. In summation, these findings suggest that VEGF-C therapy leads to enhanced post-MI lymphangiogenesis and reduces macrophage numbers in the surrounding healthy tissue. This results in decreased fibrosis of surrounding healthy tissue and improved myocardial function. These findings support the idea that therapeutic lymphangiogenesis could represent a strategy to treat myocardial infarction.

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