Claire E Trincot1, Wenjing Xu2, Hua Zhang2, Molly R Kulikauskas2, Thomas G Caranasos3, Brian C Jensen4,5,6, Amélie Sabine7, Tatiana V Petrova7,8, Kathleen M Caron1,6,9. 1. From the Curriculum in Genetics and Molecular Biology (C.E.T., K.M.C.), The University of North Carolina at Chapel Hill. 2. Department of Cell Biology and Physiology (W.X., H.Z., M.R.K.), The University of North Carolina at Chapel Hill. 3. Division of Cardiothoracic Surgery, Department of Surgery (T.G.C.), The University of North Carolina at Chapel Hill. 4. Division of Cardiology (B.C.J.), The University of North Carolina at Chapel Hill. 5. Department of Medicine, School of Medicine (B.C.J.), The University of North Carolina at Chapel Hill. 6. McAllister Heart Institute (B.C.J., K.M.C.), The University of North Carolina at Chapel Hill. 7. Department of Oncology, University of Lausanne and Lausanne University Hospital and Ludwig Institute for Cancer Research Lausanne, Switzerland (A.S., T.V.P.). 8. Division of Experimental Pathlogy, Lausanne University Hospital (T.V.P.). 9. Department of Cell Biology and Physiology (K.M.C.), The University of North Carolina at Chapel Hill.
Abstract
RATIONALE: Cardiac lymphangiogenesis contributes to the reparative process post-myocardial infarction, but the factors and mechanisms regulating it are not well understood. OBJECTIVE: To determine if epicardial-secreted factor AM (adrenomedullin; Adm=gene) improves cardiac lymphangiogenesis post-myocardial infarction via lateralization of Cx43 (connexin 43) in cardiac lymphatic vasculature. METHODS AND RESULTS: Firstly, we identified sex-dependent differences in cardiac lymphatic numbers in uninjured mice using light-sheet microscopy. Using a mouse model of Adm hi/hi ( Adm overexpression) and permanent left anterior descending ligation to induce myocardial infarction, we investigated cardiac lymphatic structure, growth, and function in injured murine hearts. Overexpression of Adm increased lymphangiogenesis and cardiac function post-myocardial infarction while suppressing cardiac edema and correlated with changes in Cx43 localization. Lymphatic function in response to AM treatment was attenuated in mice with a lymphatic-specific Cx43 deletion. In vitro experiments in cultured human lymphatic endothelial cells identified a novel mechanism to improve gap junction coupling by pharmaceutically targeting Cx43 with verapamil. Finally, we show that connexin protein expression in cardiac lymphatics is conserved between mouse and human. CONCLUSIONS: AM is an endogenous, epicardial-derived factor that drives reparative cardiac lymphangiogenesis and function via Cx43, and this represents a new therapeutic pathway for improving myocardial edema after injury.
RATIONALE: Cardiac lymphangiogenesis contributes to the reparative process post-myocardial infarction, but the factors and mechanisms regulating it are not well understood. OBJECTIVE: To determine if epicardial-secreted factor AM (adrenomedullin; Adm=gene) improves cardiac lymphangiogenesis post-myocardial infarction via lateralization of Cx43 (connexin 43) in cardiac lymphatic vasculature. METHODS AND RESULTS: Firstly, we identified sex-dependent differences in cardiac lymphatic numbers in uninjured mice using light-sheet microscopy. Using a mouse model of Adm hi/hi ( Adm overexpression) and permanent left anterior descending ligation to induce myocardial infarction, we investigated cardiac lymphatic structure, growth, and function in injured murine hearts. Overexpression of Adm increased lymphangiogenesis and cardiac function post-myocardial infarction while suppressing cardiac edema and correlated with changes in Cx43 localization. Lymphatic function in response to AM treatment was attenuated in mice with a lymphatic-specific Cx43 deletion. In vitro experiments in cultured human lymphatic endothelial cells identified a novel mechanism to improve gap junction coupling by pharmaceutically targeting Cx43 with verapamil. Finally, we show that connexin protein expression in cardiac lymphatics is conserved between mouse and human. CONCLUSIONS:AM is an endogenous, epicardial-derived factor that drives reparative cardiac lymphangiogenesis and function via Cx43, and this represents a new therapeutic pathway for improving myocardial edema after injury.
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