A regulatory role for neurokinin B in placental physiology and pre-eclampsia

Tachykinin dogma has assumed, so far, that neurokinin B (NKB) is a neuropeptide that is not produced in any peripheral tissue even though its endogenous receptor, NK3, has been found in a number of locations throughout the human body. We have found an abundant source of peripheral NKB in the human and rat placenta. In this review we describe the discovery of NKB in the placenta and examine its possible role in placental physiology and pre-eclampsia (PE). Excessive secretion of placental NKB into the maternal circulation during the third trimester of pregnancy has been found in women suffering from PE. This may provide the key to the cause of the multiple and complex symptoms associated with this potentially life-threatening illness. We also reveal the structural organisation of the human NKB gene for the first time as well as discussing putative mechanisms for its control.     

Bimodal effects of chronically administered neurokinin B (NKB) on in vivo and in vitro cardiovascular responses in female rats

The in vivo cardiovascular effects of acutely administered neurokinin B (NKB) have been attributed both to direct effects on vascular tone and to indirect effects on central neuroendocrine control of the circulation. We proposed: 1) that a modest long-term increase in plasma NKB levels would decrease mean arterial pressure (MAP) due to attenuated peripheral vascular tone, and 2) that chronic high-dose NKB would increase MAP, due to increased sympathetic outflow which would override the peripheral vasodilation. We examined the in vivo and in vitro cardiovascular effects of chronic peripheral NKB. Low- (1.8 nmol/h) or high- (20 nmol/h) dose NKB was infused into conscious female rats bearing telemetric pressure transducers. MAP, heart rate (HR) and the pressor responses to I.V. phenylephrine (PE, 8 microg) and angiotensin II (Ang II, 150 ng) were measured. Concentration-response curves of small mesenteric arteries were constructed to PE using wire myography. Low-dose NKB reduced basal MAP (88+/-2 mm Hg to 83+/-2 mm Hg), did not affect resting HR, reduced the pressor responses to PE, and attenuated the maximal constriction of mesenteric arteries to PE and KCl. By contrast, high-dose NKB increased basal MAP (86+/-1 mm Hg to 89+/-1 mm Hg), increased HR (350+/-3 beats/min to 371+/-3 beats/min), increased the pressor responses to Ang II and, contrary to our hypothesis, increased the maximum contractile responses of mesenteric arteries to PE and KCl. The cardiovascular effects of NKB are thus dose-dependent: whereas chronic low-dose NKB directly modulates vascular tone to reduce blood pressure, chronic high-dose NKB induces an increase in blood pressure through both central (indirect) and peripheral (direct) pathways.     

Tetramethylpyrazine reduces the consequences of nitric oxide inhibition in pregnant rats

Pre-eclampsia (PE) is closely associated with perinatal morbidity and mortality and we want to investigate tetramethylpyrazine (TMP)'s effects on PE. Pregnant Sprague–Dawley rats were randomly divided into five groups: normal pregnant (PC), PE, PE+TMP 20 mg/kg, PE+TMP 40 mg/kg, and PE+TMP 60 mg/kg group. The PE rat model was established via L-NAME treatment. Systolic blood pressures (SBP) and urinary protein concentration were detected via the tail-cuff method and CBB kit, respectively. mRNA levels of key genes were analyzed via quantitative PCR and protein levels of key genes were measured by ELISA or western blot. TMP decreased SBP and urinary protein concentration of PE rats. TMP inhibited L-NAME-induced decrease in pups alive ratio, pups weight, and the ratio of pups/placenta weight and reversed L-NAME induced changes in placental histology, whereas it had little effect on placental weight. Urinary nephrin and podocin expressions were enhanced and serum placental growth factor level was decreased in PE rats, whereas TMP inhibited the above phenomena. TMP suppressed L-NAME-induced sFlt-1 upregulation in serums and kidneys of PE rats, whereas it downregulated IL-6 and MCP-1 expression in PE rats' serums, placentas and kidneys. TMP also suppressed the increase in placental sFlt-1 and vascular endothelial growth factor level caused by L-NAME. In addition, TMP inhibited CHOP and GRP78 expressions and decreased the ratio of p-elF2α/elF2α in PE rats. TMP attenuated the consequences of NO inhibition in pregnant rats.     

Proteomic profiling of high glucose primed monocytes identifies cyclophilin A as a potential secretory marker of inflammation in type 2 diabetes

Hyperglycemia is widely recognized to be a potent stimulator of monocyte activity, which is a crucial event in the pathogenesis of atherosclerosis. We analyzed the monocyte proteome for potential markers that would enhance the ability to screen for early inflammatory status in Type 2 diabetes mellitus (T2DM), using proteomic technologies. Monocytic cells (THP-1) were primed with high glucose (HG), their protein profiles were analyzed using 2DE and the downregulated differentially expressed spots were identified using MALDI TOF/MS. We selected five proteins that were secretory in function with the help of bioinformatic programs. A predominantly downregulated protein identified as cyclophilin A (sequence coverage 98%) was further validated by immunoblotting experiments. The cellular mRNA levels of cyclophilin A in various HG-primed cells were studied using qRT-PCR assays and it was observed to decrease in a dose-dependent manner. LC-ESI-MS was used to identify this protein in the conditioned media of HG-primed cells and confirmed by Western blotting as well as ELISA. Cyclophilin A was also detected in the plasma of patients with diabetes. We conclude that cyclophilin A is secreted by monocytes in response to HG. Given the paracrine and autocrine actions of cyclophilin A, the secreted immunophilin could be significant for progression of atherosclerosis in type 2 diabetes. Our study also provides evidence that analysis of monocyte secretome is a viable strategy for identifying candidate plasma markers in diabetes.     

A comprehensive study of oxidative stress and antioxidant status in preeclampsia and normal pregnancy

Oxidative stress has been increasingly postulated as a major contributor to endothelial dysfunction in preeclampsia (PE), although evidence supporting this hypothesis remains inconsistent. This study aimed to analyze in depth the potential role of oxidative stress as a mechanism underlying endothelial damage in PE and the pregnant woman's susceptibility to the disease. To this end, indicative markers of lipoperoxidation and protein oxidation and changes in antioxidant defense systems were measured in blood samples from 53 women with PE and 30 healthy pregnant controls. Results, analyzed in relation to disease severity, showed PE women, compared with women with normal pregnancy, to have: (1) significantly enhanced antioxidant enzyme SOD and GPx activities in erythrocytes; (2) similar plasma alpha-tocopherol levels and significantly increased alpha-tocopherol/lipids in both mild and severe PE; (3) significantly decreased plasma vitamin C and protein thiol levels; (4) similar erythrocyte glutathione content, total plasma antioxidant capacity, and whole plasma oxidizability values; (5) significantly elevated plasma total lipid hydroperoxides, the major initial reaction products of lipid peroxidation, in severe PE; (6) no intracellular or extracellular increases in any of the secondary end-products of lipid peroxidation, malondialdehyde or lipoperoxides; (7) similar oxidative damage to proteins quantified by plasma carbonyl levels, immunoblot analysis, and advanced oxidation protein products assessment; and (8) significantly elevated and severity-related soluble vascular cell adhesion molecule-1 serum levels reflecting endothelial dysfunction. No correlations were found among plasma levels of circulating adhesion molecules with regard to lipid and protein oxidation markers. Globally, these data reflect mild oxidative stress in blood of preeclamptic women, as oxidative processes seem to be counteracted by the physiologic activation of antioxidant enzymes and by the high plasma vitamin E levels that would prevent further oxidative damage. These results do not permit us to conclude that oxidative stress might be a pathogenetically relevant process causally contributing to the disease.     

Synapsin associates with cyclophilin B in an ATP- and cyclosporin A-dependent manner

Immunophilins are ubiquitous enzymes responsible for proline isomerisation during protein synthesis and for the chaperoning of several membrane proteins. These activities can be blocked by the immunosuppressants cyclosporin A, FK506 and rapamycin. It has been shown that all three immunosuppressants have neurotrophic activity and can modulate neurotransmitter release, but the molecular basis of these effects is currently unknown. Here, we show that synapsin I, a synaptic vesicle-associated protein, can be purified from Torpedo cholinergic synaptosomes through its affinity to cyclophilin B, an immunophilin that is particularly abundant in brain. The interaction is direct and conserved in mammals, and shows a dissociation constant of about 0.5 microM in vitro. The binding between the two proteins can be disrupted by cyclosporin A and inhibited by physiological concentrations of ATP. Furthermore, cyclophilin B co-localizes with synapsin I in rat synaptic vesicle fractions and its levels in synaptic vesicle-containing fractions are decreased in synapsin knockout mice. These results suggest that immunophilins are involved in the complex protein networks operating at the presynaptic level and implicate the interaction between cyclophilin B and synapsins in presynaptic function.     

Quantitative proteomic analysis of cyclosporine-induced toxicity in a human kidney cell line and comparison with tacrolimus

The calcineurin-inhibitors (CNIs) cyclosporine (CsA) and tacrolimus (TAC) remain the pillars of modern immunosuppression regimens used in solid organ transplantation. Nephrotoxicity is an adverse effect that limits their successful use. The precise molecular mechanisms underlying this nephrotoxicity remain unclear. Using SILAC together with LC-MALDI-TOF/TOF, we investigated the CNIs-induced proteomic perturbations in renal cells. Among the 495 proteins quantifiable in both forward and reverse SILAC, 69 displayed CsA-induced perturbations: proteins involved in ER-stress/protein folding, apoptosis, metabolism/transport or cytoskeleton pathways were up-regulated, while cyclophilin B as well as nuclear and RNA-processing proteins were down-regulated. Co-administration of CsA with the antioxidant N-acetylcysteine significantly decreased lipid peroxidation and also partially corrected the CsA-induced unfolded protein response. TAC toxicity profile was apparently different from that of CsA, especially without perturbation of cyclophilins A and B, up-regulation of ER-chaperones nor down-regulation of a number of nuclear proteins. These results provide a new insight and are consistent with recent data regarding the molecular mechanisms of CNIs-induced nephrotoxicity. Our findings offer new directions for future research aiming to identify specific biomarkers of CsA nephrotoxicity.     

Differential expression of Vegfr-2 and its soluble form in preeclampsia

Background

Several studies have suggested that the main features of preeclampsia (PE) are consequences of endothelial dysfunction related to excess circulating anti-angiogenic factors, most notably, soluble sVEGFR-1 (also known as sFlt-1) and soluble endoglin (sEng), as well as to decreased PlGF. Recently, soluble VEGF type 2 receptor (sVEGFR-2) has emerged as a crucial regulator of lymphangiogenesis. To date, however, there is a paucity of information on the changes of VEGFR-2 that occur during the clinical onset of PE. Therefore, the aim of our study was to characterize the plasma levels of VEGFR-2 in PE patients and to perform VEGFR-2 immunolocalization in placenta.

Methodology/Principal findings

By ELISA, we observed that the VEGFR-2 plasma levels were reduced during PE compared with normal gestational age matched pregnancies, whereas the VEGFR-1 and Eng plasma levels were increased. The dramatic drop in the VEGFR-1 levels shortly after delivery confirmed its placental origin. In contrast, the plasma levels of Eng and VEGFR-2 decreased only moderately during the early postpartum period. An RT-PCR analysis showed that the relative levels of VEGFR-1, sVEGFR-1 and Eng mRNA were increased in the placentas of women with severe PE. The relative levels of VEGFR-2 mRNA as well as expressing cells, were similar in both groups. We also made the novel finding that a recently described alternatively spliced VEGFR-2 mRNA variant was present at lower relative levels in the preeclamptic placentas.

Conclusions/Significance

Our results indicate that the plasma levels of anti-angiogenic factors, particularly VEGFR-1 and VEGFR-2, behave in different ways after delivery. The rapid decrease in plasma VEGFR-1 levels appears to be a consequence of the delivery of the placenta. The persistent circulating levels of VEGFR-2 suggest a maternal endothelial origin of this peptide. The decreased VEGFR-2 plasma levels in preeclamptic women may serve as a marker of endothelial dysfunction.     

Mutation in cyclophilin B that causes hyperelastosis cutis in American Quarter Horse does not affect peptidylprolyl cis-trans isomerase activity but shows altered cyclophilin B-protein interactions and affects collagen folding

The rate-limiting step of folding of the collagen triple helix is catalyzed by cyclophilin B (CypB). The G6R mutation in cyclophilin B found in the American Quarter Horse leads to autosomal recessive hyperelastosis cutis, also known as hereditary equine regional dermal asthenia. The mutant protein shows small structural changes in the region of the mutation at the side opposite the catalytic domain of CypB. The peptidylprolyl cis-trans isomerase activity of the mutant CypB is normal when analyzed in vitro. However, the biosynthesis of type I collagen in affected horse fibroblasts shows a delay in folding and secretion and a decrease in hydroxylysine and glucosyl-galactosyl hydroxylysine. This leads to changes in the structure of collagen fibrils in tendon, similar to those observed in P3H1 null mice. In contrast to cyclophilin B null mice, where little 3-hydroxylation was found in type I collagen, 3-hydroxylation of type I collagen in affected horses is normal. The mutation disrupts the interaction of cyclophilin B with the P-domain of calreticulin, with lysyl hydroxylase 1, and probably other proteins, such as the formation of the P3H1·CypB·cartilage-associated protein complex, resulting in less effective catalysis of the rate-limiting step in collagen folding in the rough endoplasmic reticulum.     

The 180000 molecular weight plasma membrane insulin receptor substrate is a protein tyrosine phosphatase and is elevated in diabetic plasma membranes

Wheat germ agglutinin-purified non-diabetic and diabetic human placenta membranes were or were not depleted of EGF receptor with monoclonal anti-EGF receptor antibody B1D8, and subsequently phosphorylated. Phosphorylated insulin receptor beta-subunit was lower and pp180 was higher in diabetic placenta membranes than in non-diabetic membranes. Phosphorylated-beta-subunit was also lower in diabetic (streptozotocin-induced) rat liver whereas the amount of pp180 was dependent on membrane protein concentration. When rat liver tyrosine-phosphorylated proteins were incubated 30 min, 4 degrees C with EDTA-terminated 32P-phosphorylation reaction mixtures of wheat germ agglutinin-purified rat liver proteins, less phosphorylated proteins were immunoprecipitated with antiphosphotyrosine. The decrease in tyrosine-phosphorylated products suggested that pp180 was a protein tyrosine phosphatase. Taken together, the results suggest that diabetic plasma membranes contain more tyrosine phosphatase than non-diabetic membranes.     

Increased plasma levels of adipokines in preeclampsia: relationship to placenta and adipose tissue gene expression

Adipokines are predominantly secretory protein hormones from adipose tissue but may also originate in placenta and other organs. Cross-sectionally, we monitored maternal plasma concentration of adiponectin, resistin, and leptin and their mRNA expression in abdominal subcutaneous adipose tissue and placenta from preeclamptic (PE; n = 15) and healthy pregnant (HP; n = 23) women undergoing caesarean section. The study groups were similar in age and BMI, whereas HOMA-IR tended to be higher in the PE group. In fasting plasma samples, the PE group had higher concentrations of adiponectin (18.3 +/- 2.2 vs. 12.2 +/- 1.1 microg/ml, P = 0.011), resistin (5.68 +/- 0.41 vs. 4.65 +/- 0.32 ng/ml, P = 0.028), and leptin (34.4 +/- 3.2 vs. 22.7 +/- 2.1 ng/ml, P = 0.003) compared with the HP group. Adiponectin and leptin concentrations were still different between PE and HP after controlling for BMI and HOMA-IR, whereas resistin concentrations differed only after controlling for BMI but not HOMA-IR. We found similar mean mRNA levels of adiponectin, resistin, and leptin in abdominal subcutaneous adipose tissue in PE and HP women. When data were pooled from PE and HP women, resistin mRNA levels in adipose tissue also correlated with HOMA-IR (r = 0.470, P = 0.012) after controlling for BMI and pregnancy duration. Resistin mRNA levels in placenta were not significantly different between PE and HP, whereas leptin mRNA levels were higher in PE placenta compared with HP. Thus increased plasma concentrations of adiponectin and resistin in preeclampsia may not relate to altered expression levels in adipose tissue and placenta, whereas both plasma and placenta mRNA levels of leptin are increased in preeclampsia.     

Relationship between tissue damage and heme oxygenase expression in chorionic villi of term human placenta

Heme oxygenase (HO) catalyzes the oxidation of heme to carbon monoxide (CO), biliverdin, and iron and is thought to play a role in protecting tissues from oxidative damage. There are three isoforms of HO: HO-1 (inducible), HO-2 (constitutive), and HO-3 (unknown function). Preeclampsia is characterized by an inadequately perfused placenta and areas of tissue damage. We hypothesized that damaged areas of placentas from women with PE and uncomplicated pregnancies are associated with an alteration in HO expression. Compared with microsomes isolated from morphologically normal and peri-infarct chorionic villi of pathological placentas, microsomes from infarcted chorionic villi from the same placentas had decreased HO activity measured under optimized assay conditions. There was no correlation between microsomal HO levels and activity and tissue damage in uncomplicated pregnancies. Whereas there was no significant difference in HO-1 protein levels across all regions of uncomplicated and mildly preeclamptic pregnancies, HO-2 protein levels were decreased (P < 0.05) in peri-infarct regions and infarcted chorionic villi of mildly preeclamptic pregnancies. Immunohistochemical analysis revealed an apparent decrease in both HO-1 and HO-2 protein expression in damaged tissues. HO-1 and HO-2 were immunolocalized in the syncytiotrophoblast layer of the chorionic villi, the underlying cytotrophoblast, and in the vascular endothelium. This study suggests that the ability of the chorionic villi to oxidize heme to CO, biliverdin, and iron may be compromised in areas of tissue damage in the placenta of women with preeclampsia.     

Pulmonary vascular response to thrombin: effects of thromboxane synthetase inhibition with OKY-046 and OKY-1581

We examined the effects of thromboxane synthetase inhibition with OKY-1581 and OKY-046 on pulmonary hemodynamics and lung fluid balance after thrombin-induced intravascular coagulation. Studies were made in anesthetized sheep prepared with lung lymph fistulas. Pulmonary intravascular coagulation was induced by i.v. infusion of alpha-thrombin over a 15 min period. Thrombin infusion in control sheep resulted in immediate increases in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), which were associated with rapid 3-fold increase in pulmonary lymph flow (Qlym) and a delayed increase in lymph-to-plasma protein concentration (L/P) ratio, indicating an increase in the pulmonary microvascular permeability to proteins. Thrombin-induced intravascular coagulation also increased arterial thromboxane B2 (a metabolite of thromboxane A2) and 6-keto-PGF1 alpha concentrations (a metabolite of prostacyclin). Both OKY-1581 and OKY-046 prevented thromboxane B2 and 6-keto-PGF1 alpha generation. The initial increments in Ppa and PVR were attenuated in both treated groups. The increases in Qlym were gradual in the treated groups but attained the same levels as in control group. However, the increases in Qlym were associated with decreases in L/P ratio. In both treated groups, the leukocyte count decreased after thrombin infusion but then increased steadily above the baseline value, whereas the leukocyte count remained depressed in the control group after thrombin. These studies indicate that a part of the initial pulmonary vasoconstrictor response to thrombin-induced intravascular coagulation is mediated by thromboxane generation. In addition, thromboxane may also contribute to the increase in lung vascular permeability to proteins that occurs after intravascular coagulation and this effect may be mediated by a thromboxane-neutrophil interaction.     

Modulatory effect of grape-seed procyanidins on local and systemic inflammation in diet-induced obesity rats

Chronic low-grade inflammation in obesity is characterized by macrophage accumulation in white adipose tissue (WAT) and abnormal cytokine production. We tested the hypothesis that grape-seed procyanidin extract (PE), with known anti-inflammatory and antioxidant effects, would improve local and systemic inflammation in diet-induced obesity rats. First, we analyzed the preventive effects of procyanidins (30 mg/kg per day) on rats fed a 60% kcal fat diet for 19 weeks. Second, we induced cafeteria diet obesity for 13 weeks to investigate the corrective effects of two PE doses (25 and 50 mg/kg per day) for 10 and 30 days.In the preventive model, PE group had reduced not only body weight but also plasmatic systemic markers of inflammation tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP). The PE preventive treatment significantly showed an increased adiponectin expression and decreased TNF-α, interleukin-6 and CRP expression in mesenteric WAT and muscle TNF-α. A reduced NF-κB activity in liver is also observed which can be related to low expression rates of hepatic inflammatory markers found in PE group. Finally, PE dietary supplementation is linked to a reduced expression of Emr1 (specific marker of macrophage F4/80), which suggests a reduced macrophage infiltration of WAT.In the corrective model, however, only the high dose of PE reduced CRP plasma levels in the short treatment without changes in plasmatic TNF-α.In conclusion, orally ingested PE helps preventing imbalanced obesity cytokine pattern, but its corrective effects need to be further investigated. The dietary regular intake of food or drinks containing procyanidins might help prevent low-grade inflammatory-related diseases.     

Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat

Neurokinin B (NKB) and its cognate receptor neurokinin 3 (NK3R) play a critical role in reproduction. NKB and NK3R are coexpressed with dynorphin (Dyn) and kisspeptin (Kiss1) genes in neurons of the arcuate nucleus (Arc). However, the mechanisms of action of NKB as a cotransmitter with kisspeptin and dynorphin remain poorly understood. We explored the role of NKB in the control of LH secretion in the female rat as follows. 1) We examined the effect of an NKB agonist (senktide, 600 pmol, administered into the lateral cerebral ventricle) on luteinizing hormone (LH) secretion. In the presence of physiological levels of estradiol (E(2)), senktide induced a profound increase in serum levels of LH and a 10-fold increase in the number of Kiss1 neurons expressing c-fos in the Arc (P < 0.01 for both). 2) We mapped the distribution of NKB and NK3R mRNAs in the central forebrain and found that both are widely expressed, with intense expression in several hypothalamic nuclei that control reproduction, including the Arc. 3) We studied the effect of E(2) on the expression of NKB and NK3R mRNAs in the Arc and found that E(2) inhibits the expression of both genes (P < 0.01) and that the expression of NKB and NK3R reaches its nadir on the afternoon of proestrus (when circulating levels of E(2) are high). These observations suggest that NKB/NK3R signaling in Kiss1/NKB/Dyn-producing neurons in the Arc has a pivotal role in the control of gonadotropin-releasing hormone (GnRH)/LH secretion and its regulation by E(2)-dependent negative feedback in the rat.     

Alteration of calcium homeostasis in primary preeclamptic syncytiotrophoblasts: effect on calcium exchange in placenta

Preeclampsia (PE) is characterized by maternal hypertension, proteinuria, oedema and, in 30% of cases, by intrauterine growth retardation. Causes are still unknown; however, epidemiological and clinical studies have suggested alterations in maternal calcium metabolism. We suggested that in PE, calcium transport by the syncytiotrophoblast (ST) is disturbed. From total placental tissues, we studied the expression of: calcium channels (TRPV5, TRPV6 [transient receptor potential vanilloid]), calcium binding proteins (CaBP‐9K, CaBP‐28K), plasma membrane calcium ATPase (PMCA)1,2,3,4 pumps, ATP synthase, genes implicated in Ca²⁺ release [inositol‐1,4,5‐triphosphate receptor (IP3R)1,2,3; Ryanodine receptor (RyR)1,2,3] and replenishment (SERCA1,2,3 [sarcoendoplasmic reticulum Ca²⁺ ATPases]) from endoplasmic reticulum, channels implicated in mitochondrial Ca²⁺ accumulation (VDAC1,2,3 [voltage‐dependent anion channels]) and a marker of oxidative stress (hOGG1 [Human 8‐oxoguanine‐DNA glycosylase 1]), as well as the influence of these variations on calcium transport in primary ST cultures. The mRNA and protein levels were thereby examined by real‐time PCR and Western blot analysis, respectively, in two different groups of pregnant women with similar gestational age: a normal group (n= 16) and a PE group (n= 8), diagnosed by a clinician. Our study showed a significant decrease in calcium transport by the ST cultured from preeclamptic placentas. We found a significant (P < 0.05) decrease in mRNA levels of TRPV5, TRPV6, CaBP‐9K, CaBP‐28K, PMCA1, PMCA4, ATP synthase, IP3R1, IP3R2, RyR1, RyR2 and RyR3 in PE group compared to normal one. We also noted a significant decrease in protein levels of TRPV5, TRPV6, CaBP‐9K, CaBP‐28K and PMCA1/4 in PE group. In contrast, SERCA1, SERCA2, SERCA3, VDAC3 and hOGG1 mRNA expressions were significantly increased in PE placentas. Calcium homeostasis and transport through placenta is compromised in preeclamptic pregnancies and it appears to be affected by a lack of ATP and an excess of oxidative stress.     

Lack of Thromboxane Synthase Prevents Hypertension and Fetal Growth Restriction after High Salt Treatment during Pregnancy

Preeclampsia (PE) is a potentially fatal pregnancy-related hypertensive disorder characterized by poor placenta development that can cause fetal growth restriction. PE-associated pathologies, including thrombosis, hypertension, and impaired placental development, may result from imbalances between thromboxane A₂ (TXA₂) and prostacyclin. Low-dose aspirin, which selectively inhibits TXA₂ production, is used to prevent high-risk PE. However, the role of TXA₂ in aspirin-mediated protective effects in women with PE is not understood fully. In this study, we examined the role of prostanoids in PE using human samples and an induced PE mouse model. We demonstrated that the administration of salted drinking water (2.7% NaCl) to wild-type mice resulted in elevated placental TXA₂ synthase (TXAS) and plasma TXA₂, but not prostacyclin, levels, which was also found in our clinical PE placenta samples. The high salt-treated wild-type pregnant mice had shown unchanged maternal body weight, hypertension (MAP increase 15 mmHg), and decreased pup weight (~50%) and size (~24%), but these adverse effects were ameliorated in TXAS knockout (KO) mice. Moreover, increased expression of interleukin-1β and downstream phosphorylated-p38-mitogen-activated protein kinase were concordant with apoptosis induction in the placentas of salt water-treated wild-type mice. These alterations were not observed in TXAS KO mice. Together, our data suggest that TXA₂ depletion has anti-PE effects due to the prevention of hypertension and placental damage through downregulation of the interleukin-1β pathway.