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Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction
Florence Tatin, … , Anne-Catherine Prats, Barbara Garmy-Susini
Florence Tatin, … , Anne-Catherine Prats, Barbara Garmy-Susini
Published June 15, 2017
Citation Information: JCI Insight. 2017;2(12):e93887. https://doi.org/10.1172/jci.insight.93887.
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Research Article Vascular biology

Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction

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Abstract

Lymphatic endothelium serves as a barrier to control fluid balance and immune cell trafficking to maintain tissue homeostasis. Long-term alteration of lymphatic vasculature promotes edema and fibrosis, which is an aggravating factor in the onset of cardiovascular diseases such as myocardial infarction. Apelin is a bioactive peptide that plays a central role in angiogenesis and cardiac contractility. Despite an established role of apelin in lymphangiogenesis, little is known about its function in the cardiac lymphatic endothelium. Here, we show that apelin and its receptor APJ were exclusively expressed on newly formed lymphatic vasculature in a pathological model of myocardial infarction. Using an apelin-knockout mouse model, we identified morphological and functional defects in lymphatic vasculature associated with a proinflammatory status. Surprisingly, apelin deficiency increased the expression of lymphangiogenic growth factors VEGF-C and VEGF-D and exacerbated lymphangiogenesis after myocardial infarction. Conversely, the overexpression of apelin in ischemic heart was sufficient to restore a functional lymphatic vasculature and to reduce matrix remodeling and inflammation. In vitro, the expression of apelin prevented the alteration of cellular junctions in lymphatic endothelial cells induced by hypoxia. In addition, we demonstrated that apelin controls the secretion of the lipid mediator sphingosine-1-phosphate in lymphatic endothelial cells by regulating the level of expression of sphingosine kinase 2 and the transporter SPNS2. Taken together, our results show that apelin plays a key role in lymphatic vessel maturation and stability in pathological settings. Thus, apelin may represent a novel candidate to prevent pathological lymphatic remodeling in diseases.

Authors

Florence Tatin, Edith Renaud-Gabardos, Anne-Claire Godet, Fransky Hantelys, Francoise Pujol, Florent Morfoisse, Denis Calise, Fanny Viars, Philippe Valet, Bernard Masri, Anne-Catherine Prats, Barbara Garmy-Susini

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Figure 1

Characterization of lymphatic vasculature in adult heart.

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Characterization of lymphatic vasculature in adult heart.
(A) Immunostai...
(A) Immunostaining of a transversal cross-section through the left ventricle (LV) to examine the localization of lymphatic vessels in heart with LYVE-1 antibody (green) and the lectin wheat germ agglutinin (WGA, red). Arrows show LYVE-1–positive lymphatic vessels. (B) Whole-mount imaging of LYVE-1–positive lymphatic vessels at the epicardial surface of the heart. (C and D) Localization of capillaries and collecting lymphatic vessels with LYVE-1 antibody on paraffin cross-sections. Small lymphatic capillaries are observed in the myocardium, whereas larger vessels are located on the right ventricular side of the interventricular septum and on the subepicardial surface of the heart. Interestingly, we found the presence of lymphatic vessels at the base of mitral valve and in the tricuspid valve leaflets. (E) Identification of markers used to determine the cardiac lymphatic endothelium. NRP2, neuropilin 2; VEGFR3, vascular endothelial growth factor receptor 3; LYVE-1, lymphatic vessel endothelial hyaluronan receptor 1. Capillaries in the myocardium are defined positive for all markers except podoplanin. Larger lymphatic vessels in the septum expressed podoplanin only in the superior part of the heart. (F) Drainage of lymphatic vasculature visualized by Evans blue dye. Evans blue was injected either at the subepicardial surface of the apex or intramyocardium. (G) Schematic representation of the heart lymphatic drainage. Scale bars: 250 μm (B) and 100 μm (C and D).

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