Novel insights for the role of nitric oxide in placental vascular function during and beyond pregnancy

Abstract

More than 30 years have passed since endothelial nitric oxide synthesis was described using the umbilical artery and vein endothelium. That seminal report set the cornerstone for unveiling the molecular aspects of endothelial function. In parallel, the understanding of placental physiology has gained growing interest, due to its crucial role in intrauterine development, with considerable long-term health consequences. This review discusses the evidence for nitric oxide (NO) as a critical player of placental development and function, with a special focus on endothelial nitric oxide synthase (eNOS) vascular effects. Also, the regulation of eNOSdependent vascular responses in normal pregnancy and pregnancy-related diseases and their impact on prenatal and postnatal vascular health are discussed. Recent and compelling evidence has reinforced that eNOS regulation results from a complex network of processes, with novel data concerning mechanisms such as mechano-sensing, epigenetic, posttranslational modifications, and the expression of NO-and L-arginine-related pathways. In this regard, most of these mechanisms are expressed in an arterial-venous-specific manner and reflect traits of the fetal systemic circulation. Several studies using umbilical endothelial cells are not aimed to understand placental function but general endothelial function, reinforcing the influence of the placenta on general knowledge in physiology.

Iron nitrosyl complexes are formed from nitrite in the human placenta

“…NO and NOx species are important beyond their role in vasodilation in the placenta. NO is known to actively regulate trophoblast invasion, placental angiogenesis, and vascular development, as well as placental vascular function (3,8). Changes in placental tissue levels of eNOS and iNOS, as well as changes in plasma levels of NO metabolites, have also been observed in pregnancy pathologies such as gestational diabetes (9,10), preeclampsia (11,12), and fetal growth restriction (13,14).…”

“…The proposed mechanisms through which NO and its metabolites affect placental function include a myriad of posttranslational modifications of proteins via nitrosation of thiol residues, nitration of tyrosine residues, and nitrosylation of protein-bound iron. These modifications lead to changes in protein activity with wideranging effects on cellular homeostasis that include mitochondrial function (15), cell apoptosis (16), and histone methylation and acetylation, thus affecting the epigenetic regulation of gene expression (3,8).…”

High‐fat, sucrose and salt‐rich diet during rat spermatogenesis lead to the development of chronic kidney disease in the female offspring of the F2 generation

“…In good agreement with this hypothesis, we saw that multiple renal genes (ENPP6, TMEM144, ACTR3B, and CD300LF) and also the non‐coding RNA lncRNA XR‐146683 are associated with the development of the renal phenotype of female F2 offspring (decreased GFR, increased urinary albumin excretion, glomerulosclerosis and renal interstitial fibrosis). Alteration of just a single pathway or even single genes as a result of fetal programming events during spermatogenesis and fetal development are rather uncommon, the environmental stimuli ‐ high‐fat, high‐sucrose and high‐salt diet during spermatogenesis in two subsequent paternal generations in our case—rather induce complex epigenetic marks 4,8,36–39 inducing the observed renal phenotype. How the interaction of these different epigenetic induced alterations in various gene expression patterns in the kidney finally causes the observed renal phenotype in female F2 offspring is yet unknown.…”

Transcriptional and Epigenomic Markers of the Arterial-Venous and Micro/Macro-Vascular Endothelial Heterogeneity within the Umbilical-Placental Bed

“…The placental endothelium is multifunctional and heterogeneous, playing a key role in fetal physiology [ 1 ]. To fulfill this role, endothelial cells (EC) in the placenta show marked functional diversity, which occurs early in vascular development and allows it to cope with specific requirements in a time- and site-specific manner [ 2 ].…”

“…The latter preparation is expected to contain mainly microvessels, but it cannot distinguish the heterogeneity of EC within the villi, which is expected to have functional correlates [ 16 ]. Furthermore, if microvascular differences are based on the arterio-venous identity has not been completely addressed (reviewed in [ 1 , 2 ]). In this study, we compared transcriptomic and epigenomic profiles from umbilical and villous arteries and veins to identify molecular markers of micro- and macro-vascular heterogeneity and to uncover potential functional differences due to this heterogeneity.…”