Altered Endothelial Nitric Oxide Signaling as a Paradigm for Maternal Vascular Maladaptation in Preeclampsia

The Two Stage Model of preeclampsia proposes that a poorly perfused placenta (Stage 1) produces factor(s) leading to the clinical manifestations of preeclampsia (Stage 2). Stage 1 is not sufficient to cause the maternal syndrome but interacts with maternal constitutional factors (genetic, behavioral or environmental) to result in Stage 2. Recent information indicates the necessity for modifications of this model. It is apparent that changes relevant to preeclampsia and other implantation disorders can be detected in the first trimester, long before the failed vascular remodeling necessary to reduce placental perfusion is completed. In addition, although the factor(s) released from the placenta has usually been considered a toxin, we suggest that what is released may also be an appropriate signal from the fetal/placental unit to overcome reduced nutrient availability that cannot be tolerated by some women who develop preeclampsia. Further, it is evident that linkage is not likely to be one factor but several, different for different women. Also although the initial model limited the role of maternal constitutional factors to the genesis of Stage 2, this does not appear to be the case. It is evident that the factors increasing risk for preeclampsia are also associated with abnormal implantation. These several modifications have important implications. An earlier origin for Stage 1, which appears to be recognizable by altered concentrations of placental products, could allow earlier intervention. The possibility of a fetal placental factor increasing nutrient availability could provide novel therapeutic options. Different linkages and preeclampsia subtypes could direct specific preventive treatments for different women while the role of maternal constitutional factors to affect placentation provides targets for prepregnancy therapy. The modified Two Stage Model provides a useful guide towards investigating pathophysiology and guiding therapy.

Failure to transform uteroplacental spiral arteries is thought to underpin disorders of pregnancy, including preeclampsia and fetal growth restriction (FGR). In this study, spiral artery remodeling and extravillous-cytotrophoblast were examined in placental bed biopsies from normal pregnancy (n = 25), preeclampsia (n = 22), and severe FGR (n = 10) and then compared with clinical parameters. Biopsies were immunostained to determine vessel wall integrity, extravillous-cytotrophoblast location/density, periarterial fibrinoid, and endothelium. Muscle disruption was reduced in myometrial spiral arteries in preeclampsia (P = 0.0001) and FGR (P = 0.0001) compared with controls. Myometrial vessels from cases with birth weight 5th percentile. Fewer extravillous-cytotrophoblast surrounded both decidual and myometrial vessels in the normal group and preeclampsia group compared with the FGR group (P = 0.001). For myometrial vessels, the normal group contained more intramural extravillous-cytotrophoblast than in preeclampsia (P = 0.015). Decidual vessels in the FGR group had less fibrinoid deposition compared with controls (P = 0.013). For myometrial vessels, less fibrinoid was deposited in both the preeclampsia group (P = 0.0001) and the FGR group (P = 0.01) when compared with controls, and less fibrinoid was deposited in the preeclampsia group when compared with FGR group (P 5th percentile (P<0.02). A major defect in myometrial spiral artery remodeling occurs in preeclampsia and FGR that is linked to clinical parameters. Interstitial extravillous-cytotrophoblast is not reduced in preeclampsia but is increased in FGR.

Endothelial cells control vascular tone by releasing nitric oxide (NO) produced by endothelial NO synthase. The activity of endothelial NO synthase is modulated by the calcium concentration and by post-translational modifications (eg, phosphorylation). When NO reaches vascular smooth muscle, soluble guanylyl cyclase is its primary target producing cGMP. NO production is stimulated by circulating substances (eg, catecholamines), platelet products (eg, serotonin), autacoids formed in (eg, bradykinin) or near (eg, adiponectin) the vascular wall and physical factors (eg, shear stress). NO dysfunction can be caused, alone or in combination, by abnormal coupling of endothelial cell membrane receptors, insufficient supply of substrate (l-arginine) or cofactors (tetrahydrobiopterin), endogenous inhibitors (asymmetrical dimethyl arginine), reduced expression/presence/dimerization of endothelial NO synthase, inhibition of its enzymatic activity, accelerated disposition of NO by reactive oxygen species and abnormal responses (eg, biased soluble guanylyl cyclase activity producing cyclic inosine monophosphate) of the vascular smooth muscle. Major culprits causing endothelial dysfunction, irrespective of the underlying pathological process (aging, obesity, diabetes mellitus, and hypertension), include stimulation of mineralocorticoid receptors, activation of endothelial Rho-kinase, augmented presence of asymmetrical dimethyl arginine, and exaggerated oxidative stress. Genetic and pharmacological interventions improve dysfunctional NO-mediated vasodilatations if protecting the supply of substrate and cofactors for endothelial NO synthase, preserving the presence and activity of the enzyme and reducing reactive oxygen species generation. Common achievers of such improvement include maintained levels of estrogens and increased production of adiponectin and induction of silent mating-type information regulation 2 homologue 1. Obviously, endothelium-dependent relaxations are not the only beneficial action of NO in the vascular wall. Thus, reduced NO-mediated responses precede and initiate the atherosclerotic process.