Fetal Loss of Adrenomedullin Causes Maternal Vascular Pathology Typical of Preeclampsia.

Abstract

Adrenomedullin (AM) is a 52-amino acid peptide vasodilator that is elevated 3 to 5-fold in normal human pregnancies but is often blunted in pregnancy complications such as fetal growth restriction, gestational diabetes, and preeclampsia. Our previous studies have shown that genetic reduction of maternal AM leads to poor pregnancy outcomes, but the role of fetal AM remains unknown. Therefore, we examined placentas of Adm-/- and Adm+/+ pups at midgestation for structural, functional, and developmental phenotypes. Histologic and morphometric analysis revealed normal differentiation and layer formation in the Adm-/- placentas. Doppler ultrasound of umbilical cord blood flow showed that placental impedance was unaffected by fetal loss of Adm. Although histology and lectin staining showed no difference in the total cross-sectional area of fetal and maternal vessels, the fetal vessels of the Adm-/- placentas were large and underbranched compared to those of wildtype littermates. Electron microscopy of methyl-methacrylate casts confirmed that Adm-/- placentas had reduced fetal vessel branching; a hallmark feature of preeclampsia. Strikingly, the Adm-/- placentas also had reduced numbers of decidual natural killer (NK) cells and reduced remodeling of maternal spiral arteries; other known features of preeclampsia. To further investigate the effects of AM signaling on NK cells, isolated primary NK cells were treated with AM, which resulted in significantly altered cytokine expression compared to untreated controls. Primary smooth muscle cell cultures exposed to supernatant from AM-treated NK cells also showed a significant increase in smooth muscle cell apoptosis, indicating that the AM-mediated change in NK cell cytokine expression may be required for normal spiral artery remodeling. To confirm that this phenotype is specific to lack of fetal AM, ovarian transplantation was performed from Adm+/- to Adm+/+ females. The placentas of Adm-/- pups from wildtype mothers receiving heterozygote ovary transplants recapitulated the reduced NK cell invasion and failed spiral artery remodeling originally seen in heterozygous mothers, demonstrating that lack of AM specifically from the fetal compartment is responsible for the observed preeclampsia-like pathology. Furthermore, we were able to rescue this phenotype by generating a transgenic mouse model with increased fetal AM expression, termed Admhi/hi. High fetal AM led to recruitment of increased decidual NK cells and normal spiral artery remodeling. RT-PCR screening revealed that numerous cytokines known to play important roles in the placenta had opposite regulation in Admhi/hi versus Adm-/- placentas. Taken together, these data indicate that loss of fetal AM causes reduced fetal vascularization and maternal spiral artery remodeling characteristic of preeclampsia, and that these phenotypes can be rescued by overexpressing fetal AM. These findings demonstrate that the dosage of fetal AM is a critical factor for adapting the maternal vasculature to pregnancy and may be important in preventing the development of preeclampsia. This work is supported by The Burroughs Wellcome Fund, NIH/NICHD RO1 HD46970, HD060860, NIH/NHLBI F30 HL104778, and the March of Dimes Foundation. (poster)