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Abstract
Heart has a wide lymphatic network but the importance of cardiac lymphatic system in heart diseases has remained unclear. Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) is a key molecule in the development and maintenance of cardiac lymphatic vessels. Here we characterized the role of VEGFR3 in healthy hearts and after myocardial infarction (MI) by using sVEGFR3 transgenic mice expressing a soluble decoy VEGFR3 under K14 promoter and Chy mice which have an inactivating mutation in the VEGFR3 gene. Cardiac lymphatic vessels were significantly dilated in the healthy hearts of sVEGFR3 mice when compared to controls. Lymphatic vessels formed large sheet-like structures in Chy mice. Attenuated VEGFR3 signaling led to a more severe MI predisposing to a significantly higher mortality in sVEGFR3 mice than in control mice. sVEGFR3 mice displayed intramyocardial hemorrhages in the infarcted area indicating hyperpermeability of the vasculature. Furthermore, novel MRI methods TRAFF2 and TRAFF4 and histological analysis revealed a modified structure of the fibrotic infarcted area in sVEGFR3 mice. In conclusion, the downregulation of VEGFR3 signaling modifies the structure of cardiac lymphatic network and causes vascular leakiness and increased mortality after MI.
Highlights
Lymphatic vessels were long considered as passive drainage conduits of extracellular fluid but their role has been extended since the mechanisms of their development and function in several pathophysiological processes have been identified[1]
This might be explained by a higher proportion of the larger infarction areas in soluble decoy VEGFR3 (sVEGFR3) mice than in control mice: 40.9% of sVEGFR3 mice had infarction areas spanning more than 20% of the LV wall (LVW), whereas only 27.2% of control mice had these large infarcted areas (Fig. 1b)
We have studied the role of vascular endothelial growth factor receptor 3 (VEGFR3) in cardiac lymphatic vessels and in healing after myocardial infarction (MI)
Summary
Lymphatic vessels were long considered as passive drainage conduits of extracellular fluid but their role has been extended since the mechanisms of their development and function in several pathophysiological processes have been identified[1]. The effect of cardiac lymph flow impairment has been studied by blocking ventricular and mediastinal lymphatic ducts in large animals (reviewed by Cui[14]) In these studies, the obstruction of lymphatic flow led to subepicardial edema, depressed left ventricle (LV) contractile function and hemorrhages. Lymphangiogenic therapy with vascular endothelial growth factor receptor 3 (VEGFR3)-specific vascular endothelial growth factor C (VEGF-C) protein improved LV function after MI in mice[9] and resolved cardiac edema and fibrosis in rats[16] It has recently been shown in a human phase 1 clinical trial that the gene transfer of another VEGFR3 ligand, VEGF-D, improves cardiac blood flow in refractory angina patients[17]. After MI, sVEGFR3 mice had significantly higher mortality than the control littermates, intramyocardial hemorrhages, a reduced capability to respond to lymphangiogenic signals and a modified structure of the infarcted area
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