Placental Ischemia Says “NO” to Proper NOS-Mediated Control of Vascular Tone and Blood Pressure in Preeclampsia

Abstract

In this review, we first provide a brief overview of the nitric oxide synthase (NOS) isoforms and biochemistry. This is followed by describing what is known about NOS-mediated blood pressure control during normal pregnancy. Circulating nitric oxide (NO) bioavailability has been assessed by measuring its metabolites, nitrite (NO2) and/or nitrate (NO3), and shown to rise throughout normal pregnancy in humans and rats and decline postpartum. In contrast, placental malperfusion/ischemia leads to systemic reductions in NO bioavailability leading to maternal endothelial and vascular dysfunction with subsequent development of hypertension in PE. We end this article by describing emergent risk factors for placental malperfusion and ischemic disease and discussing strategies to target the NOS system therapeutically to increase NO bioavailability in preeclamptic patients. Throughout this discussion, we highlight the critical importance that experimental animal studies have played in our current understanding of NOS biology in normal pregnancy and their use in finding novel ways to preserve this signaling pathway to prevent the development, treat symptoms, or reduce the severity of PE.

Increased NOS coupling by the metabolite tetrahydrobiopterin (BH4) reduces preeclampsia/IUGR consequences

“…It has also been suggested to treat PE by modulating the NOS coupling [9,12,13]. Indeed, NOS coupled to its cofactors produces NO, whereas uncoupled NOS produce NO as well as the superoxide anion (O 2 − ), a ROS.…”

Ultrasound-based radiomics model: a potential adjunctive tool for assessing impaired placental function in preeclampsia

“…The placental Atlas Tool was also developed to create a shared platform for placental data research 36 . Additionally, previous studies have demonstrated a strong association between the onset and progression of preeclampsia and placental dysfunction during early pregnancy [37][38][39] . The placenta in pregnancies affected by preeclampsia undergoes a constantly changing and unhealthy metabolic state throughout gestation 40 .…”

Paradoxes: Cholesterol and Hypoxia in Preeclampsia

“…Treatment of caveolae with oxidized LDL also ablates NOS3 activity, which can be restored by cholesterol treatment [137] [138] [139]. Studies of mice with absent NOS3 function show an exaggerated response to VEGF blocking factors with increased hypertension, hepatic dysfunction, thrombocytopenia, and renal dysfunction [140], all symptoms of human preeclampsia.…”