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Review
. 2021 Oct 19;22(20):11261.
doi: 10.3390/ijms222011261.

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

Ana C Palei  1 , Joey P Granger  2 , Frank T Spradley  1   2   3
Affiliations
Review

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

Ana C Palei et al. Int J Mol Sci. .

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.

Keywords: intrauterine growth restriction; nitric oxide; nitric oxide synthases; potential therapies; preeclampsia; pregnancy.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Schematic representation of the cascade of events leading from trophoblast dysfunction and cellular stress to subsequent abnormalities in uteroplacental vascular remodeling, malperfusion, and ischemia. These ischemia/hypoxic events elicit the release of anti-angiogenic and pro-hypertensive factors, like soluble Fms-like tyrosine kinase (sFlt-1), into the maternal circulation. This factor can feedback to reduce cellularity of the placenta, and reduce uteroplacental vascularity [24]. sFlt-1 can also quench vasodilatory factors, like PlGF, which are important for maternal vascular health. This ultimately leads to systemic reductions in nitric oxide (NO) bioavailability and endothelial dysfunction. Reduced NO has less capacity to activate its receptor, soluble guanylate cyclase (sGC), and production of the second messenger cyclic guanosine monophosphate (cGMP) resulting in maternal vascular dysfunction, hypertension, and intrauterine growth restriction (IUGR). In red font is the proposal that administration of NOS substrates or cofactors; modulators of sGC; or blocking the breakdown of cGMP with inhibitors of phosphodiesterase (PDE)-5 could be utilized to prevent the development, treat symptoms, or reduce the severity of PE.
Figure 2
Figure 2
Impact of non-selective NOS inhibition with L-NAME on conscious maternal mean arterial blood pressure (MAP). L-NAME was administered in pregnant rats from gestational day 13–19 in drinking water (Vehicle). * p < 0.05 for virgin vs. pregnant vehicle-treated rats; ** p < 0.05 for pregnant + vehicle vs. pregnant + L-NAME rats. Mean ± SEM. Data adapted from [25].
Figure 3
Figure 3
Effects of treatment with recombinant human placental growth factor (rhPlGF) on blood pressure responses in pregnant rats with reduced uterine perfusion pressure (RUPP). Rats were subjected to the RUPP procedure on gestational day 14. Rats were administered rhPlGF (180 μg/kg per day, I.P. osmotic minipump) from gestational day 14–19. Conscious mean arterial blood pressure (MAP) was measured on day 19. p-Values appear in the above brackets. Mean ± SEM. Data adapted from [116].
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