Sildenafil for the Treatment of Preeclampsia, an Update

Should We Still Be Enthusiastic?

Noémie Simon-Tillaux; Edouard Lecarpentier; Vassilis Tsatsaris; Alexandre Hertig


Nephrol Dial Transplant. 2019;34(11):1819-1826. 

In This Article

Preeclampsia: From Placenta Dysfunction to Maternal Pathological Endothelium

In endothelial cells, NO is a gas produced from L-arginine by endothelial NO synthase (eNOS), and its biological effect on smooth muscle cells is mediated by cGMP (Figure 1). cGMP decreases calcium content that induces relaxation of the vasculature.[23] AngII acts in just the opposite way: the binding of its receptor (ATR1) induces phospholipase C and D (PLC, PLD), which increases intracellular calcium content through lipid messengers, and induces a potent contraction of smooth muscle cells. In preeclampsia, endothelin-1 production by the endothelium in response to AngII fuels the same signalling pathways of AngII in smooth muscle cells through the endothelin receptor type A (ETA), thus potentializing its vasoconstrictor effect (Figure 2).

Figure 2.

Synergy of AngII and endothelin-1 (ET-1) in vascular contraction and their pathologic effect in preeclampsia. The AngII receptor ATR1 is located on both the endothelial and smooth muscle cell membranes. Among its effects, AngII induces the production of ET-1 by the endothelial cells through its receptor ATR1; the two peptidic hormones then participate together in the contraction of smooth muscle cells. The fixation of AngII and ET-1 to ATR1 and ETA, respectively, leads to stimulation of PLC, PLD via ATR1 or ETA-coupled protein G. These two enzymes cut membranous phospholipids. The PLC converts phosphatidylinositol 4,5-bisphosphate into inositol triphosphate (IP3), which opens a specific calcium channel on the sarcoplasmic reticulum (IP3R), increasing cytoplasmic Ca2+ concentration and promoting myosin fibre contraction, thence into diacylglycerol (DAG), which activates phosphokinase C (PKC), which subsequently induces myosin light-chain phosphatase (MLCP) inactivation. The PLD acts in a similar way by indirectly converting the phosphatidic acid into DAG. These two mechanisms are Gq-dependently strengthened by the opening of the voltage-dependent L-type Ca2+ channel, with the entrance of Ca2+ from the extracellular space into the cytoplasmic compartment, and activation of the Rho signalling pathway, inhibiting MLCP. Altogether these processes contribute to smooth muscle cell contraction [20,26]. In pregnancy, circulating levels of both AngII and NO are elevated, the combination resulting in a relative resistance to AngII-dependent contraction. However, in preeclampsia, NO contents decrease secondary to the placental secretion of sFlt-1. The soluble receptor traps VEGF, thus preventing endothelial NO production and subsequently leading to more cleavage by the ACE of AngI into AngII, as NO may act as an inhibitor of the enzyme. AngII can also activate Rho member A (RhoA) by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which generates reactive oxygen species (ROS), thus sustaining the state of contraction. The NO deprivation amplifies this last phenomenon as the gas can act as a scavenger for ROS [27].

AngII is produced from the cleavage of angiotensinogen into angiotensin I (AngI) by renin and then converted into AngII by angiotensin-converting enzyme (ACE). When transgenic mice expressing human angiotensinogen are fertilized with transgenic males expressing human renin (with the consequent placenta also expressing human renin), a preeclamptic phenotype is seen.[28] Although the clinical significance is poorly understood, some preeclamptic women display activating autoantibodies directed against ATR1, which is capable of inducing its heterodimerization with the bradykinin β2-receptor and which results in an increased response to AngII (despite lower levels in preeclamptic patients).[29,30] A state of relative vasodilation is another potential mechanism for the loss of resistance to vasopressors, particularly to AngII, observed in preeclampsia compared with normal pregnancy.[31] Interestingly, this abnormal sensitivity to AngII lasts beyond delivery: it is still observed in the skin microvasculature of women with a recent (6 months) history of preeclampsia and is borderline significant for mean arterial pressure 5 years after the event.[32,33] Nevertheless, targeting AngII or the use of ACE is not realistic in pregnant women because of associated severe cardiac and renal defects in the offspring.[34,35]

Conversely, pregnant women exhibit increased activation of eNOS (through increased phosphorylation); this advantage is lost, however, at the very beginning of preeclampsia.[19,36] Increased production by preeclamptic placentas of soluble endoglin (sENG), the soluble form of the endothelial receptor of transforming growth factor beta (TGF-β), is involved in reduced eNOS activity.[29] By trapping TGF-β and VEGF, sENG and sFlt-1, respectively, thus both contribute to impaired eNOS phosphorylation.

Rats in which preeclampsia is induced by the viral administration of human sFlt-1, sensitivity to AngII is reestablished.[19] In another model of (mild) preeclampsia, induced by a systemic deficiency in catechol-O-methyl transferase (COMT), mice also displayed AngII hypersensitivity[37] and an increase (~20% at Day 17 of gestation) in sFlt-1 concentration.[38] COMT is the enzyme that catalyzes the conversion of 2-hydroxyestradiol into 2-methoxyestradiol (2-ME). Mechanistically, 2-ME induces proliferating peroxisome-activated receptor gamma, a transcription factor that represses ATR1.[37,38] COMT-deficient mice logically exhibit an increased sensitivity to AngII. In both models of preeclampsia—COMT knockout and human sFlt-1 overexpression—SC reduces this vascular hypersensitivity to vasoconstrictors.[19,39]

How exactly NO modulates the endothelial sensitivity to AngII is not fully elucidated. NO decreases the activity of ACE and the conversion from AngI to AngII[40] and also acts as a scavenger of oxidants, which are required for AngII-induced hypertension.[41]