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.
Highlights
The number of hypertensive pregnancies has been on the rise over the past several decades
In its active form, nitric oxide synthase (NOS) is a homodimer where each subunit is composed of a C-terminal reductase domain, which comprises the binding sites for nicotinamide adenine dinucleotide phosphate (NADPH), flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD), and by an N-terminal oxygenase domain, which contains binding sites for of 22 heme, zinc, tetrahydrobiopterin (BH4), and L-arginine
Telemetric evidence supports the development of placental ischemia-induced hypertension in reduced uterine uterine perfusion perfusion pressure pressure (RUPP) rats [113], which is accompanied by reduced NOS-mediated buffering of vascular tone and increased vasoconstriction [114]
Summary
The number of hypertensive pregnancies has been on the rise over the past several decades. Damage to the fetal-derived trophoblast cells that reside in the placenta and decidualized uterus is thought to mediate and propagate the maternal vascular dysfunction and hypertensive outcomes in PE, regardless of its gestational age of presentation [6,7] Such damage can result from multiple factors, including malperfusion and resultant placental ischemia. We end this article by describing emergent risk factors for placental malperfusion and ischemic disease and discuss strategies to therapeutically target the NOS system 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
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