Epicardial‐derived adrenomedullin drives cardiac hyperplasia during embryogenesis

Abstract

Background Growth promoting signals from the epicardium are essential for driving myocardial proliferation during embryogenesis. In adults, these signals become reactivated following injury and promote angiogenesis and myocardial repair. Therefore, identification of such paracrine factors could lead to novel therapeutic strategies. The multi-functional peptide adrenomedullin (Adm = gene, AM = protein) is required for normal heart development. Moreover, elevated plasma AM following myocardial infarction offers beneficial cardioprotection and serves as a powerful diagnostic and prognostic indication of disease severity. Results Here, we developed a new model of Adm overexpression by stabilizing the Adm mRNA through gene-targeted replacement of the endogenous 3′ untranslated region. As expected, Admhi/hi mice express three-times more AM than controls in multiple tissues, including the heart. Despite normal blood pressures, Admhi/hi mice unexpectedly showed significantly enlarged hearts due to increased cardiac hyperplasia during development. The targeting vector was designed to allow for reversion to wild-type levels by means of Cre-mediated modification. Using this approach, we demonstrate that AM derived from the epicardium, but not the myocardium or cardiac fibroblast, is responsible for driving cardiomyocyte hyperplasia. Conclusions AM is produced by the epicardium and drives myocyte proliferation during development, thus representing a novel and clinically relevant factor potentially related to mechanisms of cardiac repair after injury.

Decoy Receptor CXCR7 Modulates Adrenomedullin-Mediated Cardiac and Lymphatic Vascular Development

“…AM binds RDC1/CXCR7 with a K d of 1.9 ×10 −7 M, similar to CLR when associated with RAMPs (Kapas and Clark, 1995). Importantly, we have recently shown that genetic overexpression of AM ligand in Adm hi/hi mice results in gross cardiac enlargement due to cardiac hyperplasia during embryogenesis (Wetzel-Strong et al, 2013), which closely phenocopies the dysmorphic cardiac hyperplasia of Cxcr7 −/− mice.…”

Adrenomedullin and endocrine control of immune cells during pregnancy

“…26 AM RECRUITMENT OF UNK CELLS IS DOSAGE-DEPENDENT Subsequent studies of a gene-targeted murine model of Adm overexpression (Adm hi allele, which expresses Adm at levels three-fold higher than the wild-type allele) determined that uNK cell recruitment to the decidua by AM is dosage-dependent. 5,28 Specifically, Adm hi/hi placentas demonstrated a 30% increase in uNK cells. 28 Because the uNK cells in these placentas were labeled with Dolichos biflorus agglutinin lectin, we can conclude that the uNK cell population that was quantified is, in fact, the one that expands during pregnancy.…”

“…4,5 AM belongs to the calcitonin/calcitonin gene-related peptide family, which binds various combinations of G-coupled protein receptors and their associated receptor activity modifying proteins. The canonical receptor for AM is calcitonin receptor-like receptor when associated with either receptor activity modifying protein 2 or 3.…”

Adrenomedullin in lymphangiogenesis: from development to disease

“…This difficulty was particularly apparent in Cxcr7-null mice, which exhibited cardiac enlargement and hyperplasia, a phenotype that was not observed in mutant mice of the canonical ligands, SDF-1 and CXCL11 [21,61,62]. However, the cardiac phenotypes closely phenocopied a genetic model of AM overexpression (known as Adm hi/hi mice) which results in gross cardiac hyperplasia during embryogenesis [25,63]. The similarity in cardiac phenotypes and the historical association of AM and CXCR7 sparked curiosity about whether CXCR7 could behave as a decoy receptor for AM.…”

“…It will be interesting to tease out whether levels of AM originating outside of the tumor impact cancer progression via lymphangiogenesis. Adm overexpression models may prove useful in determining host AM status on tumor progression [63].…”