NAD depletion is central to placental dysfunction in an inflammatory subclass of preeclampsia.

Preeclampsia (PE) is a hypertensive disorder of pregnancy and a major cause of maternal/perinatal adverse health outcomes with no effective therapeutic strategies. Our group previously identified distinct subclasses of PE, one of which exhibits heightened placental inflammation (inflammation-driven PE). In non-pregnant populations, chronic inflammation is associated with decreased levels of cellular NAD, a vitamin B3 derivative involved in energy metabolism and mitochondrial function. Interestingly, specifically in placentas from women with inflammation-driven PE, we observed the increased activity of NAD-consuming enzymes, decreased NAD content, decreased expression of mitochondrial proteins, and increased oxidative damage. HTR8 human trophoblasts likewise demonstrated increased NAD-dependent ADP-ribosyltransferase (ART) activity, coupled with decreased mitochondrial respiration rates and invasive function under inflammatory conditions. Such adverse effects were attenuated by boosting cellular NAD levels with nicotinamide riboside (NR). Finally, in an LPS-induced rat model of inflammation-driven PE, NR administration (200 mg/kg/day) from gestational days 1-19 prevented maternal hypertension and fetal/placental growth restriction, improved placental mitochondrial function, and reduced inflammation and oxidative stress. This study demonstrates the critical role of NAD in maintaining placental function and identifies NAD boosting as a promising preventative strategy for PE.