Orianne Henri1, Chris Pouehe1, Mahmoud Houssari1, Ludovic Galas1, Lionel Nicol1, Florence Edwards-Lévy1, Jean-Paul Henry1, Anais Dumesnil1, Inès Boukhalfa1, Sébastien Banquet1, Damien Schapman1, Christian Thuillez1, Vincent Richard1, Paul Mulder1, Ebba Brakenhielm1. 1. From Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Rouen, France (O.H., C.P., M.H., L.N., J.-P.H., A.D., I.B., S.B., C.T., V.R., P.M., E.B.); Normandy University & University of Rouen, Institute for Research and Innovation in Biomedicine, France (O.H., C.P., M.H., L.G., L.N., J.-P.H., A.D., I.B., S.B., D.S., C.T., V.R., P.M., E.B.); PRIMACEN, Cell Imaging Platform of Normandy, Inserm, Mont-Saint-Aignan, France (L.G., D.S.); PICTUR, In Vivo Imaging Platform, University of Rouen, Institute for Research and Innovation in Biomedicine, France (L.N., C.T., P.M.); Reims Institute of Molecular Chemistry, UMR 7312 CNRS-URCA, University of Reims Champagne Ardenne, France (F.E.-L,); and Rouen University Hospital, Department of Pharmacology, France (C.T.).
Abstract
BACKGROUND: The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI. METHODS AND RESULTS: We investigated cardiac lymphatic structure and function in rats with MI induced by either temporary occlusion (n=160) or permanent ligation (n=100) of the left coronary artery. Although MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial precollector and collector lymphatics occurred, leading to reduced cardiac lymphatic transport capacity. Consequently, myocardial edema persisted for several months post-MI, extending from the infarct to noninfarcted myocardium. Intramyocardial-targeted delivery of the vascular endothelial growth factor receptor 3-selective designer protein VEGF-CC152S, using albumin-alginate microparticles, accelerated cardiac lymphangiogenesis in a dose-dependent manner and limited precollector remodeling post-MI. As a result, myocardial fluid balance was improved, and cardiac inflammation, fibrosis, and dysfunction were attenuated. CONCLUSIONS: We show that, despite the endogenous cardiac lymphangiogenic response post-MI, the remodeling and dysfunction of collecting ducts contribute to the development of chronic myocardial edema and inflammation-aggravating cardiac fibrosis and dysfunction. Moreover, our data reveal that therapeutic lymphangiogenesis may be a promising new approach for the treatment of cardiovascular diseases.
BACKGROUND: The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI. METHODS AND RESULTS: We investigated cardiac lymphatic structure and function in rats with MI induced by either temporary occlusion (n=160) or permanent ligation (n=100) of the left coronary artery. Although MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial precollector and collector lymphatics occurred, leading to reduced cardiac lymphatic transport capacity. Consequently, myocardial edema persisted for several months post-MI, extending from the infarct to noninfarcted myocardium. Intramyocardial-targeted delivery of the vascular endothelial growth factor receptor 3-selective designer protein VEGF-CC152S, using albumin-alginate microparticles, accelerated cardiac lymphangiogenesis in a dose-dependent manner and limited precollector remodeling post-MI. As a result, myocardial fluid balance was improved, and cardiac inflammation, fibrosis, and dysfunction were attenuated. CONCLUSIONS: We show that, despite the endogenous cardiac lymphangiogenic response post-MI, the remodeling and dysfunction of collecting ducts contribute to the development of chronic myocardial edema and inflammation-aggravating cardiac fibrosis and dysfunction. Moreover, our data reveal that therapeutic lymphangiogenesis may be a promising new approach for the treatment of cardiovascular diseases.
Authors: Xiaolei Liu; Xiaowu Gu; Wanshu Ma; Michael Oxendine; Hyea Jin Gil; George E Davis; Ondine Cleaver; Guillermo Oliver Journal: Development Date: 2018-08-20 Impact factor: 6.868
Authors: Claire E Trincot; Wenjing Xu; Hua Zhang; Molly R Kulikauskas; Thomas G Caranasos; Brian C Jensen; Amélie Sabine; Tatiana V Petrova; Kathleen M Caron Journal: Circ Res Date: 2019-01-04 Impact factor: 17.367