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

Abstract

Rationale: Cardiac lymphangiogenesis contributes to the reparative process post myocardial infarction (MI), but the factors and mechanisms regulating it are not well understood. Objective: To determine if epicardial-secreted factor adrenomedullin (AM=protein; Adm=gene) improves cardiac lymphangiogenesis post-MI via lateralization of Connexin43 (Cx43) 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 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 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, 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.

Human cardiac fibroblasts expressing VCAM1 improve heart function in postinfarct heart failure rat models by stimulating lymphangiogenesis

“…Cardiac lymphangiogenesis plays a central role in maintaining fluid homeostasis for healthy heart contraction [18]. Recent studies have suggested that lymphangiogenesis improves cardiac function and healing by draining accumulated fluids and maintaining the physiological interstitial fluid equilibrium [19,20,70]. These studies, together with our RNA sequencing data, suggested that VCFs have a favorable expression of genes related to the regulation of blood and/or lymph vessel formation.…”

“…In this study, VCF treatment appeared to efficiently mobilize LECs in the infarct zone (Fig 6), but there was no significant difference between the VCF and control groups in the extent of fibrosis (Fig 5). Similarly, Trincot et al reported that adrenomedullin overexpression induces mouse cardiac lymphangiogenesis after myocardial infarction, but the area of fibrosis is not changed [70]. Although further studies are necessary to understand the relations between lymphangiogenesis and fibrosis, regulatory T cells seems involved as they have been shown to improve cardiac function after myocardial infarction via the inhibition of inflammation and the attenuation of interstitial fibrosis [16,77].…”

Metoprolol protects against myocardial infarction by inhibiting miR-1 expression in rats

“…[7] Studies have reported that the elevation of Cx43 could effectively reduce ventricular arrhythmias in MI model due to increased conduction velocity and intercellular coupling. [9,38,39] Trincot et al [18] reported that increased gap junction coupling induced by Cx43 between human lymphatic endothelial cells helped endogenous lymphangiogenic response that preserve cardiac function and reduce oedema after MI. Here, we demonstrated that overexpression of miR-1 abolished metoprolol's effect on enhancing intercellular communication, which may be attributed to inhibition of Cx43.…”

“…[15] Cx43 has been identified as a direct target of miR-1 [16] and is proved as a key therapeutic target in ischaemia/reperfusion injury [17] as well as MI. [18] Here, we determined the effects of b1-blocker metoprolol on expression of miR-1 and Cx43 in heart tissue of MI rats. As shown in Figure 3a and b, miR-1 expression was remarkably up-regulated while Cx43 was down-regulated in MI group.…”

The Interplay Between E-Cadherin, Connexin 43, and Zona Occludens 1 in Retinal Pigment Epithelial Cells

“…Of all currently identified connexin genes, connexin 43 is the most extensively expressed and has been investigated in the most detail. [6][7][8] Connexin 43 observed in RPE 4,9 is capable of mediating intercellular dye transfer 4 and protecting against oxidative stress-induced cell death. 9 Zona occludens 1 (ZO-1) was one of the first recognized and best-studied tight junction proteins.…”