The role of lymphangiogenesis in cardiovascular diseases and heart transplantation

Abstract

Cardiac lymphangiogenesis plays an important physiological role in the regulation of interstitial fluid homeostasis, inflammatory, and immune responses. Impaired or excessive cardiac lymphatic remodeling and insufficient lymph drainage have been implicated in several cardiovascular diseases including atherosclerosis and myocardial infarction (MI). Although the molecular mechanisms underlying the regulation of functional lymphatics are not fully understood, the interplay between lymphangiogenesis and immune regulation has recently been explored in relation to the initiation and development of these diseases. In this field, experimental therapeutic strategies targeting lymphangiogenesis have shown promise by reducing myocardial inflammation, edema and fibrosis, and improving cardiac function. On the other hand, however, whether lymphangiogenesis is beneficial or detrimental to cardiac transplant survival remains controversial. In the light of recent evidence, cardiac lymphangiogenesis, a thriving and challenging field has been summarized and discussed, which may improve our knowledge in the pathogenesis of cardiovascular diseases and transplant biology.

Keywords: Atherosclerosis; Cardiovascular diseases; Heart transplantation; Lymphangiogenesis; Myocardial infarction; VEGF-C/VEGFR-3.

Fig. 1

Lymphatics of cardiac muscles in C57BL/6 J mice. Immunofluorescence staining with the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1, green) for lymphatics, CD31 (red) for blood vessels, and 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI, blue) for nuclear counterstaining in the cardiac muscle (A ~ H). Initial lymphatics are mainly surrounding myocardial fibers, and fewer than the blood capillaries (A ~ D). Moreover, the relationship between irregular collecting lymphatics and blood vessels is clearly identified in perimysial connective tissues of the heart (E ~ H)

Fig. 2

Transmission electron micrographs (TEM) of the intermuscular lymphangiomas in the diaphragm of BALB/c mice. Near abdominal muscular fibers of the diaphragm, the endothelial cells are decorated with LYVE-1 and 5′-nucleotidase (5′-Nase)-cerium reactive precipitates (A–C) to confirm new formation of initial lymphatics. The developmental lymphatic structures have a definite endothelial lining with simple intercellular junctions (B, C, arrows). Lv lymphatic vessels, Bv blood vessels

Fig. 3

Schematic diagram depicting the lymphangiogenesis regulated by several kinds of cytokines, chemokines, and growth factors has emerged as a major therapeutic or interventional target in cardiovascular diseases and heart transplantation