Abstract
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.
Highlights
Myocardial infarction (MI) is a common cardiac emergency with the potential for substantial morbidity and mortality [2]
We demonstrate that combination of lymphatic endothelial progenitor cells (LEPCs) transplantation and vascular endothelial growth factor C (VEGF-C) release with self-assembling peptide (SAP) is effective for enhancing cardiac lymphangiogenesis, reducing cardiac edema and inflammation, attenuating reverse myocardial remodeling and improving cardiac function post-MI
Our findings provide the first evidence for cardiac lymphangiogenesis participated by bone marrow-derived LEPCs. CD34+VEGFR-3+ EPCs isolated from the mononuclear cells of bone marrow express Prox1 and have a potential to differentiate towards lymphatic endothelial cells
Summary
Myocardial infarction (MI) is a common cardiac emergency with the potential for substantial morbidity and mortality [2]. After occlusion of a coronary artery or its branch, necrosis of myocardium triggers local inflammation, scar formation and remodeling of the ventricular wall. The patients die of heart failure or arrhythmia . Regeneration of the post-infarct myocardium and angiogenesis are vital processes in repair of the infarcted myocardium. Physiopathologic impacts of cardiac lymphangiogenesis on prognosis of patients with MI have been ignored. There are the subendocardial, myocardial and subepicardial networks of the lymphatic capillaries. Lymph flow in cardiac chambers is from the endocardium
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