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Published Manuscript

Cardiac lymphatics form a vast plexus of vasculature essential to normal cardiac fluid homeostasis and immune cell clearance. Cardiac lymphangiogenesis contributes to the reparative process post myocardial infarction (MI), but the factors and mechanisms regulating it are not well understood. Lymphatics are regulated via many innate hormonal and sex-dependent factors, but sex differences are vastly understudied in the field of lymphatic biology. These studies identified sex-dependent differences in cardiac lymphatic development. Using a mouse model of adrenomedullin (AM=protein; Adm=gene) overexpression (Admhi/hi) and permanent left anterior descending (LAD) ligation to induce MI, we investigated cardiac lymphatic structure, growth, and function in injured murine hearts. Overexpression of Adm increased lymphangiogenesis and cardiac function post-MI while suppressing cardiac edema and correlated with changes in Connexin 43 (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 (hLECs) identified a novel mechanism to improve gap junction coupling by pharmaceutically targeting Cx43 with verapamil. Finally, experiments show that connexin protein expression in cardiac lymphatics are conserved between mouse and human. Using both gain- and loss-of-function mouse models, these studies also sought to elucidate how AM signaling in the epicardium contributes to cardiovascular and cardiac lymphatic development. Microarray analysis attempted to elucidate genetic targets of AM during cardiovascular development. In vitro studies show that AM activation of ERK may drive cardiomyocyte proliferation. Epicardial deletion of AM’s receptor, Calcrl, led to delayed cardiovascular development in embryos and increased cardiac lymphatics in female mice. AM is an endogenous, epicardial-derived factor that drives reparative and developmental cardiac lymphangiogenesis and function via Cx43, representing a novel cardiovascular therapeutic pathway.