Impairment of cardiac lymphatic vessels leads to cardiac
lymphedema. Recent studies have suggested that stimulation of lymphangiogenesis may reduce cardiac
lymphedema. However, effects of lymphatic endothelial progenitor cells (LEPCs) on cardiac lymphangiogenesis are poorly understood. Therefore, this study investigated effectiveness of LEPC
transplantation and
VEGF-C release with self-assembling
peptide (SAP) on cardiac lymphangiogenesis after
myocardial infarction (MI). CD34+VEGFR-3+ EPCs isolated from rat bone marrow differentiated into lymphatic endothelial cells after
VEGF-C induction.
VEGF-C also stimulated the cells to incorporate into the lymphatic capillary-like structures. The functionalized SAP could adhere with the cells and released
VEGF-C sustainedly. In the condition of
hypoxia and serum deprivation or abdominal pouch assay, the SAP
hydrogel protected the cells from apoptosis and
necrosis. At 4 weeks after intramyocardial
transplantation of the cells and
VEGF-C loaded with SAP
hydrogel in rat MI models, cardiac lymphangiogenesis was increased,
cardiac edema and reverse remodeling were reduced, and cardiac function was improved significantly. Delivery with SAP
hydrogel favored survival of the engrafted cells.
VEGF-C released from the
hydrogel promoted differentiation and incorporation of the cells as well as growth of pre-existed lymphatic vessels. Cardiac lymphangiogenesis was beneficial for elimination of the inflammatory cells in the infarcted myocardium. Moreover, angiogenesis and myocardial regeneration were enhanced after reduction of
lymphedema. These results demonstrate that the combined delivery of LEPCs and
VEGF-C with the functionalized SAP promotes cardiac lymphangiogenesis and repair of the infarcted myocardium effectively. This study represents a novel
therapy for relieving myocardial
edema in
cardiovascular diseases.