Molecular Basis of Adrenomedullin 1 Receptor Function and Its Roles in the Cardiovascular System

Adrenomedullin (AM), a hypotensive peptide, exerts powerful anti-oxidative, anti-inflammatory and antiatherosclerotic effects. In addition, AM strongly acts as an angiogenic and lymphangiogenic growth factor. Therefore, AM has attracted a great deal of attention as a potential therapeutic agent against cardiovascular diseases, such as acute myocardial infarction, heart failure, arteriosclerosis obliterans, pulmonary hypertension and secondary lymphedema. There are two receptor subtypes for AM, both of which are formed by the association of receptor activity-modifying proteins (RAMP2 or RAMP3), which are single transmembrane domain accessory proteins, with calcitonin receptor-like receptor (CLR), a G protein-coupled receptor. The CLR/RAMP2 and CLR/RAMP3 complexes form the AM1 and AM2 receptors, respectively. The specificity of AM for the AM1 receptor is higher than that for the AM2 receptor, which is conserved across multiple animal species. The AM1 receptor is essential for the development of the fetal cardiovascular system. Moreover, overexpression of the AM1 receptor in the vascular smooth muscle cell layers of the aorta can augment AM-induced blood pressure reduction and almost completely inhibit aortic vascular hypertrophy and inflammation caused by chronic angiotensin II infusion. Notably, the AM-AM1 receptor system was found to be crucially involved in both angiogenesis and lymphangiogenesis. In contrast, the cardiovascular functions of the AM2 receptor remain unclear, although there have been no reports showing differences in intracellular signaling via the two AM receptors. In this review, we focus on the molecular basis of AM1 receptor function and its roles in the cardiovascular system and also discuss the possibility of related drug discovery.