Adrenomedullin (AM) is a 52-amino acid peptide vasodilator that is elevated in the serum during normal human pregnancies but is often blunted in pregnancy complications including preeclampsia. One hallmark feature of preeclampsia is failure of uterine spiral arteries to remodel, a process that depends on uterine natural killer (uNK) cells. Our previous studies revealed that placentas lacking AM exhibit failed spiral artery remodeling and reduced maternal uNK cells. We sought to determine whether there are dosage-related effects of AM on the placenta through the use of a mouse model that overexpresses AM (Admhi/hi), and found that Admhi/hi placentas have a significant increase in uNK cell numbers. Furthermore, fetal AM dosage alters the immune milieu of the placenta, as numerous chemokines and cytokines are oppositely regulated in Admhi/hi versus Adm+/- placentas. We also investigated a variety of single nucleotide polymorphisms in the AM signaling system in a human population, and found that several polymorphisms in AM and its signaling components are significantly associated with adverse pregnancy outcomes. Together, these findings support the central role of AM in human pregnancy and pregnancy complications. One component of the AM signaling system is receptor activity modifying protein 3 (RAMP3), a molecular chaperone known to interact with and affect the trafficking of several G protein-coupled receptors (GPCRs). We investigated whether RAMP3 interacts with G protein-coupled receptor 30 (GPR30), a GPCR that binds estradiol and has important roles in cardiovascular and endocrine physiology. We found that GPR30 and RAMP3 interact in vitro, and the presence of GPR30 leads to increased expression of RAMP3 at the plasma membrane. In vivo, there are marked sex differences in the subcellular localization of GPR30 in cardiac cells, and the hearts of Ramp3-/- mice also show signs of GPR30 mislocalization. Next, we treated Ramp3+/+ and Ramp3-/- mice on a heart disease-prone genetic background with a specific agonist for GPR30. Importantly, activation of GPR30 resulted in a significant reduction in cardiac hypertrophy and perivascular fibrosis that is both RAMP3- and sex-dependent. Thus, the GPR30-RAMP3 interaction has functional consequences on the localization of these proteins and RAMP3 is required for GPR30-mediated cardioprotection.