PLACENTAL AND FETAL RESPONSES TO ADRENOMEDULLIN DEFICIENCY IN THE RAT

Adrenomedullin (ADM) is a peptide hormone with a broad spectrum of actions on vascular smooth muscle, endothelial cells, and immune cells. These ADM cellular targets are prominent constituents of the uterine-placental interface that undergo structural and functional transformation during pregnancy. To explore the biology of ADM at the uterine-placental interface, we examined ADM expression using in situ hybridization and generated and characterized an ADM mutant rat model using CRISPR-Cas9-mediated genome editing. At midgestation, Adm was prominently expressed in trophoblast giant cells. Adm expression shifted to the mesometrial uterus as gestation progressed. A germline Adm mutant model was generated. Adm heterozygous males and females were fertile; however, Adm heterozygous intercrosses did not generate live Adm null rats. Adm null fetal-placental sites were viable until gestation day (gd) 15.5. Viable null fetuses were not identified after gd 15.5. Fetal and placental growth restriction were evident on gd 13.5. On gd 15.5 some Adm null placentas exhibited prominent hemorrhagic regions, whereas both hemorrhage and edema were evident in gd 15.5 Adm null fetuses. Our results indicate that ADM serves as a regulator of placental and fetal development.