Hypothesis: inhibition of endothelium-derived relaxing factor by haemoglobin in the pathogenesis of pre-eclampsia

doi:10.1016/0140-6736(90)92490-9

The Lancet

Volume 336, Issue 8722, 27 October 1990, Pages 1030-1032

https://doi.org/10.1016/0140-6736(90)92490-9 Get rights and content

Abstract

Although the aetiology of pre-eclampsia is unknown, haemodynamic studies suggest that many of the clinical findings may be explained by a generalised vasoconstrictive disorder and abnormal endothelial cell function. Vasoconstriction may be attributed to the increased concentrations of haemoglobin found in pre-eclampsia compared with normal pregnancy. Free haemoglobin may be derived from haemolysis and placental haemorrhage and, at concentrations known to be present in pre-eclampsia, vasodilatation mediated by endothelium-derived relaxing factor is inhibited. Infusion of oxyhaemoglobin into human coronary arteries inhibits acetylcholine-induced vasodilatation. We suggest that an increased free haemoglobin concentration is the cause of vasoconstriction in pre-eclampsia.

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Cited by (62)

Circular RNA expression profiling identifies hsa_circ_0011460 as a novel molecule in severe preeclampsia
2019, Pregnancy Hypertension
Citation Excerpt :
This finding indirectly suggests that vasodilation and regulation of blood vessel size may be involved in the onset of PE. In addition, clinical studies [23,24] reported that maternal endothelial function and aberrant concentrations of the endogenous inhibitor of endothelial nitric oxide synthase (ADMA) were associated with PE. Huang et al. [25] reported that PE is associated with impaired maternal-foetal nutrient transfer, and the amino acid transporters SLC7A7 and SLC38A5 showed marked differences between controls and PE.
To identify circRNA expression profiles in the placentae of severe preeclampsia (SPE) and normal pregnant (NP) women.
Placental samples were collected from six paired SPE and NP women. CircRNA expression profiles were identified by RNA-Seq and validated in another 30 SPE and NP samples by qRT-PCR. Several bioinformatic tools were utilised to analyse the potential function of differentially expressed circRNAs (DE-circRNAs) and to predict target microRNAs (miRNAs) and proteins. Furthermore, immunohistochemistry, Western blotting and RNA binding protein immunoprecipitation (RIP) were conducted to confirm the interaction between the circRNA and protein.
In total, 18,631 circRNAs were detected. Among them, 180 circRNAs were differentially expressed, including 94 upregulated and 86 downregulated circRNAs. Seven DE-circRNAs were selected for validation, and the results of six circRNAs (hsa_circ_0007611, hsa_circ_0011460, hsa_circ_0002888, and hsa_circ_0007445, hsa_circ_0017068, hsa_circ_0012737) were consistent with the sequencing results. Bioinformatics analyses of DE-circRNAs revealed that most of them are involved in vasodilation, regulation of blood vessel size, protein transport and localization, and pathways in cancer. In addition to the mRNA expression profile, it was interesting to find that the hsa_circ_0011460 target gene solute carrier organic anion transporter family member 2A1 (SLCO2A1, PGT) was also significantly increased in SPE placentae. Immunohistochemistry, Western blotting and qRT-PCR validated the expression and distribution of PGT. Finally, RIP of HTR-8/SVneo cells confirmed that hsa_circ_0011460 targets PGT directly.
A total of 180 DE-circRNAs were detected. One crucial circRNA, hsa_circ_0011460, was shown to interact directly with its host gene PGT. These findings indicated that hsa_circ_0011460 may serve as a potential therapeutic target for patients with SPE.
Is there a link between endothelial dysfunction, coagulation activation and nitric oxide synthesis in preeclampsia?
2013, Clinica Chimica Acta
Citation Excerpt :
NO could react rapidly with hemoglobin iron instead of the reaction between iron from guanylate cyclase. The inactivation of NO by hemoglobin iron in PE was previously raised by Sarrel et al. [38]. Second, several studies on women with PE suggested a relationship between enhanced O2− generation and endothelial injury, inflammation [39] as well as a decreased superoxide dismutase [40].
There may be a relationship between endothelial dysfunction, coagulation activation and nitric oxide (NO) synthesis in women with mild and severe preeclampsia (PE).
Plasma thrombomodulin (TM), D-Dimer (D-Di), cyclic guanosine monophosphate (cGMP) and placental nitric oxide synthase activity (NOS) were investigated in 21 normotensive pregnant women (G1), 22 pregnant women with mild PE (G2) and 20 pregnant women with severe PE (G3).
TM and D-Di were significantly increased in G3 compared to G1 (P = 0.001 and P = 0.006, respectively) and G2 (P = 0.001, in both cases). However, there was no significant difference when G1 was compared to G2. For total NOS, calcium independent NOS, calcium dependent NOS no significant difference was observed among the groups studied.
TM and D-Di levels are raised in women with severe PE compared to normotensive pregnant women and women with mild PE. While increased TM levels may reflect endothelial dysfunction, raised D-Di levels indicate a hypercoagulable state. NO assessed by 2 indirect methods did not show any significant difference among the groups studied. Due to current limitations with in vitro NO measurements and interferences associated with NO bioavailability, particularly in PE, such findings should not be over-interpreted.
Circulating microparticles in severe preeclampsia
2012, Clinica Chimica Acta
Citation Excerpt :
Our data showed increased number of erythrocyte-derived MPs in women with severe PE. This finding could be explained by hemolysis, which is commonly observed in this disease [28]. Because fibrin clots have been observed in the microvasculature of women with PE, one hypothesis is that erythrocytes are lysed by colliding with such clots and result in MP release [29].
The present study aimed to evaluate microparticles (MPs) from different sources in women with severe preeclampsia (PE) compared with normotensive pregnant women and non-pregnant women. This case–control study evaluated 28 pregnant women with severe PE, 30 normotensive pregnant women, and 29 non-pregnant women. MPs from neutrophils, endothelial cells, monocytes, platelets, leukocytes, erythrocytes, and syncytiotrophoblast were evaluated using flow cytometry. A higher total number of MPs were observed in women with severe PE compared with normotensive pregnant women and non-pregnant women (P = 0.004 and P = 0.001, respectively). MPs derived from erythrocytes were increased in women with severe PE compared with normotensive pregnant women (P = 0.002). A trend towards association was observed between platelet count and the number of MPs derived from platelets (P = 0.09) in severe PE group. A positive correlation was also found between the number of endothelial cell-derived MPs and the number of platelet-derived MPs, leukocyte-derived MPs, neutrophil-derived MPs, and lymphocyte-derived MPs (P < 0.05) in severe PE pregnant women. MP counts can be increased in severe PE, and erythrocyte and endothelial cell-derived MPs seem to be associated to severe PE.
Increased circulating cell-free hemoglobin levels reduce nitric oxide bioavailability in preeclampsia
2010, Free Radical Biology and Medicine
Contrasting with increased nitric oxide (NO) formation during healthy pregnancy, reduced NO bioavailability plays a role in preeclampsia. However, no study has examined whether increased NO consumption by enhanced circulating levels of cell-free hemoglobin plays a role in preeclampsia. We studied 82 pregnant women (38 healthy pregnant and 44 with preeclampsia). To assess NO bioavailability, we measured plasma and whole blood nitrite concentrations using an ozone-based chemiluminescence assay. Plasma ceruloplasmin concentrations and plasma NO consumption (pNOc) were assessed and plasma hemoglobin (pHb) concentrations were measured with a commercial immunoassay. We found lower whole blood and plasma nitrite concentrations in preeclamptic patients (-48 and -39%, respectively; both P < 0.05) compared with healthy pregnant women. Plasma samples from preeclamptic women consumed 63% more NO (P = 0.003) and had 53% higher pHb and 10% higher ceruloplasmin levels than those found in healthy pregnant women (P < 0.01). We found significant positive correlations between pHb and pNOc (r = 0.61; P < 0.0001), negative correlations between pNOc and whole blood or plasma nitrite concentrations (P = 0.02; r = -0.32 and P = 0.01; r = -0.34, respectively), and negative correlations between pHb and whole blood or plasma nitrite concentrations (P = 0.03; r = -0.36 and P = 0.01; r = -0.38, respectively). These findings suggest that increased pHb levels lead to increased NO consumption and lower NO bioavailability in preeclamptic compared with healthy pregnant women.
Cerebral haemodynamic pathologies in HELLP syndrome
2003, Clinical Neurology and Neurosurgery
The syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP syndrome) is understood as a unique variant of severe preeclampsia. This disorder complicates between 2 and 7% of gestations and is associated with a high perinatal morbidity and a maternal morbidity ranging between 1 and 4%. Intracerebral complications only rarely occur, especially intracerebral haemorrhage was described only in single cases, often correlated with fatal maternal outcome. The analysis of patients with HELLP syndrome treated at our hospital revealed three cases with severe neurological deterioration. Possible pathogenetic factors are discussed.
Blood glutathione redox status in gestational hypertension
2001, Free Radical Biology and Medicine
Gestational hypertension during the third trimester reflects an exaggerated maternal inflammatory response to pregnancy. We hypothesized that oxidative stress present even in normal pregnancy becomes uncompensated in hypertensive patients. A glucose-6-phosphate dehydrogenase (G6PD) activity sufficient to meet the increased reductive equivalent need of the cells is indispensable for defense against oxidative stress. The erythrocyte glutathione redox system was studied, where G6PD is the only NADPH source. The glutathione (GSH) redox status was measured both in vivo and after an in vitro oxidative challenge in pregnant women with gestational hypertension (n = 19) vs. normotensive pregnant subjects (n = 18) and controls (n = 20). An erythrocyte GSH depletion with an increase in the oxidized form (GSSG) resulted in an elevated ratio GSSG/GSH (0.305 ± 0.057; mean ± SD) in hypertensive pregnant women vs. normotensive pregnant or control subjects (0.154 ± 0.025; 0.168 ± 0.073; p < .001). In hypertensive pregnant patients, a “GSH stability” decrease after an in vitro oxidative challenge suggested a reduced GSH recycling capacity resulting from an insufficient NADPH supply. The erythrocyte GSSG/GSH ratio may serve as an early and sensitive parameter of the oxidative imbalance and a relevant target for future clinical trials to control the effects of antioxidant treatment in women at increased risk of the pre-eclampsia syndrome.

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Hypothesis: inhibition of endothelium-derived relaxing factor by haemoglobin in the pathogenesis of pre-eclampsia

Abstract

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

JACC

Lancet

Am J Obstet Gynecol

Am J Obstet Gynecol

Biochem Biophys Acta

Lancet

Vasorelaxant properties of the endothelium-derived relaxing factor more closely resemble S-nitrosocysteine than nitric oxide

Nature

Haptoglobinhaemoglobin complex in human plasma inhibits endothelium dependent relaxation: evidence that endothelium derived relaxing factor acts as a local autocoid

Cardiovasc Res