Adrenomedullin Induces Cardiac Lymphangiogenesis After Myocardial Infarction and Regulates Cardiac Edema Via Connexin 43

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.