Roles of CLR/RAMP receptor signaling in reproduction and development

Adrenomedullin (ADM), calcitonin gene-related peptides (α- and β-CGRPs), and intermedin/adrenomedullin 2 (IMD/ADM2) are major regulators of vascular tone and cardiovascular development in vertebrates. Recent research into their functions in reproduction has illuminated the role of these peptides and their cognate receptors (calcitonin receptor-like receptor/receptor activity-modifying protein (CLR/RAMP) receptors) in fetal-maternal blood circulation, fetoplacental development, female gamete development, and gamete movement in the oviduct. Although ADM family peptides function in a temporally and spatially specific manner in various reproductive processes, they appear to act via a similar set of second messengers, including nitric oxide, cyclic GMP, cyclic AMP, and calcium-activated potassium channels in different tissues. These discoveries supported the view that CLR/RAMP receptors were recruited to perform a variety of newly evolved reproductive functions during the evolution of internal reproduction in mammals. These advances also provided insight into how CLR/RAMP receptor signaling pathways coordinate with other physiological adaptions to accommodate the extra metabolic needs during pregnancy, and captured some important details as to how fetal-maternal vascular communications are generated in the first place. Furthermore, these findings have revealed novel, promising opportunities for the prevention and treatment of aberrant pregnancies such as pregnancy-induced hypertension, preeclampsia, and tubal ectopic pregnancy. However, significant efforts are still needed to clarify the relationships between certain components of the CLR/RAMP signaling pathway and aberrant pregnancies before CLR/RAMP receptors can become targets for clinical management. With this understanding, this review summarizes recent progresses with particular focus on clinical implications.