AHR activated placental adrenomedullin: A plausible factor in smoke-induced preeclampsia protection

The placenta develops as trophectoderm cells invade and secrete peptides to remodel the maternal vasculature. Impaired invasion can lead to preeclampsia. Maternal smoking during pregnancy can cause miscarriage and fetal developmental problems. Yet curiously, cigarette use during pregnancy correlates with a decreased risk for preeclampsia. To explore this, we have studied the secreted peptide, adrenomedullin (ADM) that promotes placentation and is increased by maternal smoking. The aryl hydrocarbon receptor (AHR) is a transcription factor that binds cigarette-associated carcinogenic ligands. We hypothesized that AHR activation by cigarette smoke induces Adm to promote placental development.

Pregnant transgenic animals exhibiting overexpression of Adm or genetic loss of Ahr were exposed to cigarette smoke. Embryo and placenta tissues were evaluated. Immortalized trophoblast cells (HTR8/SVneo) were also exposed to cigarette smoke extract before AHR chromatin immunoprecipitation with quantitative polymerase chain reaction.

Ablation of Ahr reduced embryo weights and embryo/placental weight ratios. Further, overexpression of Adm increased placental weights in sham treated conditions yet caused abnormal placental growth and stunted embryo development with cigarette smoke. Finally, chromatin immunoprecipitation results demonstrated that AHR significantly binds to two sites on the ADM promoter.

In a mouse model of high Adm expression, cigarette smoke can elicit stunted embryo and placental weights and abnormal placental morphology. Thus, tightly regulated ADM levels are critical for murine gestational development and in the presence of cigarette smoke, are promoted by AHR-mediated transcriptional activation. These studies provide compelling results suggesting AHR drives ADM upregulation in the smoke-exposed placenta.