Increased vascular and uteroplacental matrix metalloproteinase-1 and -7 levels and collagen type I deposition in hypertension in pregnancy: role of TNF-α.

Preeclampsia is a pregnancy-related disorder manifested as maternal hypertension in pregnancy (HTN-Preg) and fetal growth restriction. Placental ischemia could be an initiating event that leads to abnormal vascular and uteroplacental remodeling in HTN-Preg; however, the molecular targets and intermediary mechanisms involved are unclear. We tested the hypothesis that placental ischemia could target vascular and uteroplacental matrix metalloproteinases (MMPs) through an inflammatory cytokine-mediated mechanism. MMP levels and distribution were measured in the aorta, uterus, and placenta of normal pregnant (Preg) rats and pregnant rats with reduced uterine perfusion pressure (RUPP). Maternal blood pressure was higher and the litter size and pup weight were lower in RUPP compared with Preg rats. Gelatin zymography showed prominent uterine MMP-2 and MMP-9 activity that was dependent on the amount of loaded protein. At saturating protein loading, both gelatin and casein zymography revealed two additional bands corresponding to MMP-1 and MMP-7 that were greater in the aorta, uterus, and placenta of RUPP compared with Preg rats. Western blots and immunohistochemistry confirmed increased MMP-1 and MMP-7 in the aorta, uterus, and placenta of RUPP versus Preg rats. The levels of MMP-1 and MMP-7 substrate collagen type I were greater in tissues of RUPP compared with Preg rats. In organ culture, TNF-α increased MMP-1 and MMP-7 in the aorta, uterus, and placenta of Preg rats, and a TNF-α antagonist prevented the increases in MMPs in tissues of RUPP rats. Thus, placental ischemia, possibly through TNF-α, increases vascular and uteroplacental MMP-1 and MMP-7, which, in turn, alter collagen deposition and cause inadequate tissue remodeling in HTN-Preg. Cytokine antagonists may reverse the increase in MMP-1 and MMP-7 expression/activity and, in turn, restore proper vascular and uteroplacental remodeling in HTN-Preg and preeclampsia.NEW & NOTEWORTHY The molecular mechanisms of preeclampsia are unclear, making it difficult to predict, prevent, or manage the pregnancy-associated disorder. This study showed that placental ischemia, possibly through the release of TNF-α, causes increases in the levels of matrix metalloproteinase (MMP)-1 and MMP-7, which could alter collagen deposition and cause inadequate uteroplacental and vascular remodeling in hypertension in pregnancy. The data suggest that targeting MMP-1 and MMP-7 and their upstream modulators, such as TNF-α, could provide a new approach in the management of hypertension in pregnancy and preeclampsia.

Hydrogen inhibits cytotrophoblast cells apoptosis in hypertensive disorders complicating pregnancy.

Hypertensive disorders complicating pregnancy (HDCP) is one of the most serious medical disorders during pregnancy. Hydrogen is a therapeutic antioxidant and used to treat HDCP effectively. However, the molecular mechanism about the effect of hydrogen on HDCP still remains unclear. In this study, we found ROS content in HDCP group was significantly higher than that in the control and was reduced markedly in the presence of 100µmol/L hydrogen. IL6, Caspase3, Bax1, P-JAK2, P-Stat3 and P-p38 expression was much higher than the control, and was notably decreasedby the application of 100µmol/L hydrogen. Bcl2 expression in HDCP group was notably lower than the control and was increased by 100 µmol/L hydrogen. The apoptosis rate of cytotrophoblast cells was decreased, andratio of cytotrophoblast cells at G1 and G2 phase was increased and decreased by hydrogen, respectively. All those data indicated a potential molecular mechanism of hydrogen-mediated treatment in HDCP.

Urinary excretion of brush-border enzymes of the proximal renal tubules in pregnant women with hypertensive disorders.

OBJECTIVES: The aim of our study was to evaluate urinary excretion of three brush border enzymes: gamma-glutamyl transferase, alanine aminopeptidase, and leucyl aminopeptidase in pregnant women with various types of hypertensive disorders. MATERIAL AND METHODS: The study included 120 pregnant women, further subdivided into four groups: 41 women at ≥ 20 weeks gestation with gestational hypertension, 28 women > 20 weeks of pregnancy with preeclampsia, 21 women with chronic hypertension identified > 20 weeks of pregnancy and 30 healthy pregnant controls. RESULTS: No significant differences in urinary levels of all three of the brush border enzymes were found between the groups. Also, there was no correlation between enzyme concentration in the urine and blood pressure values in any of the analyzed groups of pregnant women. CONCLUSIONS: The obtained results suggest no damage to the brush border of the proximal kidney tubules in the early stages of disorders associated with increased blood pressure during pregnancy.

Localization of folate metabolic enzymes, methionine synthase and 5,10-methylenetetrahydrofolate reductase in human placenta.

BACKGROUND: Normal fetal development requires adequate folate levels during pregnancy. Although folate metabolic enzymes have important roles in the maintenance of normal fetal development, the location of folate metabolic enzymes, methionine synthase (MTR) and 5,10-methylenetetrahydrofolate reductase (MTHFR), has not been previously examined. METHODS: We investigated the expression of MTR and MTHFR in human term placenta obtained from normal and pregnancy-induced hypertension (PIH) patients. RESULTS: MTR is expressed in the villous syncytiotrophoblast and MTHFR is expressed in the extravillous trophoblast. There was no difference in the quantity and location of these enzymes between control and PIH patients. CONCLUSION: These results suggest that MTR in the villous trophoblast participates in the metabolism of homocysteine by using folate, and MTHFR in the extravillous trophoblast is associated with extratrophoblast invasion.

Matrix metalloproteinase-9 polymorphisms affect plasma MMP-9 levels and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy.

Abnormal matrix metalloproteinase (MMP)-9 levels may have a role in hypertensive disorders of pregnancy. We examined whether MMP-9 genetic polymorphisms (g.-1562C >T and g.-90(CA)13-25) modify plasma MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 levels and the responses to antihypertensive therapy in 214 patients with preeclampsia (PE), 185 patients with gestational hypertension (GH) and a control group of 214 healthy pregnant (HP). Alleles for the g.-90(CA)13-25 polymorphism were grouped L (low) (< 21 CA repeats) or H (high) (≥ 21 CA repeats). Plasma MMP-9 and TIMP-1 concentrations were measured by enzyme-linked immunosorbent assay. Plasma MMP-9 concentrations were not affected by genotypes or haplotypes in HP and PE groups, except for the g.-90(CA)13-25 polymorphism: GH patients with the LH genotype for this polymorphism have higher MMP-9 levels than those with other genotypes. The T allele for the g.-1562C > T polymorphism and the H4 haplotype (combining T and H alleles) are associated with GH and lack of responsiveness to antihypertensive therapy in GH. The H2 haplotype (combining C and H alleles) was associated with lack of responsiveness to antihypertensive therapy in PE, but not in GH. In conclusion, our results show that MMP-9 genetic variants are associated with GH and suggest that MMP-9 haplotypes affect the responsiveness to antihypertensive therapy in hypertensive disorders of pregnancy.

Association between matrix metalloproteinase (MMP)-2 polymorphisms and MMP-2 levels in hypertensive disorders of pregnancy.

We examined whether two functional polymorphisms (g.-1306C>T and g.-735C>T) in matrix metalloproteinase (MMP)-2 gene are associated with preeclampsia (PE) or gestational hypertension (GH), and whether they modify MMP-2 or tissue inhibitor of metalloproteinase (TIMP)-2 plasma concentrations in these hypertensive disorders of pregnancy. We studied 130 healthy pregnant (HP), 130 pregnant with GH, and 133 pregnant with PE. Genomic DNA was extracted from whole blood and genotypes for g.-1306C>T and g.-735C>T polymorphisms were determined by Real Time-PCR, using Taqman allele discrimination assays. Haplotypes were inferred using the PHASE program. Plasma MMP-2 and TIMP-2 concentrations were measured by ELISA. The main findings were that pregnant with PE have higher plasma MMP-2 and TIMP-2 concentrations than HP (P<0.05), although the MMP-2/TIMP-2 ratios were similar (P>0.05). Moreover, pregnant with GH have elevated plasma MMP-2 levels and MMP-2/TIMP-2 ratios compared to HP (P<0.05). While MMP-2 genotypes and haplotypes are not linked with hypertensive disorders of pregnancy, MMP-2 genotypes and haplotypes are associated with significant alterations in plasma MMP-2 and TIMP-2 concentrations in preeclampsia (P<0.05). Our findings may help to understand the relevance of MMP-2 and its genetic polymorphisms to the pathophysiology of hypertensive disorders of pregnancy. It is possible that patients with PE and the MMP-2 haplotype combining the C and T alleles for the g.-1306C>T and g.-735C>T polymorphisms may benefit from the use of MMPs inhibitors such as doxycycline. However, this possibility remains to be determined.

Paeoniflorin alleviates NG-nitro-L-arginine methyl ester (L-NAME)-induced gestational hypertension and upregulates silent information regulator 2 related enzyme 1 (SIRT1) to reduce H2O2-induced endothelial cell damage.

Pregnancy-induced hypertension (PIH) is a leading cause of maternal mortality. Paeoniflorin has been reported to alleviate hypertension, thus relieving the injury of target organ. This study aimed to investigate the role of paeoniflorin in PIH development by regulating SIRT1 in rats. The mean arterial pressure (MAP), urine protein and histopathological damage of placenta in gestational hypertension rats were, respectively, detected by noninvasive tail-artery pressure measuring instrument, BCA method and H&E staining. The viability of human umbilical vein endothelial cells (HUVECs) treated with paeoniflorin or/and H2O2 was observed by CCK-8 assay. SIRT1 protein expression in HUVECs treated with paeoniflorin or/and H2O2 was analyzed by Western blot. Tunel assay, wound healing assay and tube formation assay were used to detect the apoptosis, migration and tube formation of HUVECs administrated with paeoniflorin or/and H2O2 or/and EX527 (SIRT1 inhibitor). As a result, MAP, urine protein and histopathological damage of placenta were enhanced in PIH rats, which were then alleviated by paeoniflorin. Paeoniflorin decreased the levels of sFlt-1, PlGF and VEGF in serum and placental tissues of gestational hypertension rats as well as the inflammatory response and oxidative stress. In addition, paeoniflorin promoted the expressions of SIRT1 and NO/eNOS and inhibited the production of iNOS in gestational hypertension rats to improve vascular endothelial cell injury. However, SIRT1 inhibition could suppress the protective effects of paeoniflorin on endothelial dysfunction of H2O2-induced HUVECs. In conclusion, paeoniflorin could improve gestational hypertension development by upregulating SIRT1.

Impaction of factors associated with oxidative stress on the pathogenesis of gestational hypertension and preeclampsia: A Chinese patients based study.

ABSTRACT: We aimed to investigate the effect of Kelch-like ECH-associated protein 1/NF-E2 p45-related factor 2 (Keap1/Nrf2) pathway on the biological function of trophoblast cells in oxidative stress model at the cellular level, and analyzed the expression level and clinical significance of Keap1/Nrf2 pathway and related antioxidant factors in placental tissues of Preeclampsia (PE) patients at clinical level. In present study, we found that under hypoxia/reoxygenation conditions, the activity of oxidative stress-related enzymes (CAT, GSH-Px, SOD) in HTR8/SVneo cells was significantly lower than that before treatment (P < .01). The activities of CAT, GSH-Px and SOD in HTR8/SVneo cells in SiRNA+H/R group decreased significantly (P < .01), indicating the important defense effect of Keap1/Nrf2 signaling pathway in oxidative stress. As a control group of Nrf2 SiRNA+H/R group, Si-NC+H/R group had CAT, GSH-Px and SOD activities decreasing, which was similar to that in H/R group. Moreover, the activities of oxidative stress-related active enzymes in patients with PE were further confirmed by detecting and comparing the activities of CAT, GSH-Px and SOD in placental tissues. The results showed that the activity of SOD (P < .001), GSH-Px (P < .01) and CAT (P < .01) in placental tissues of patients with PE were significant different from those of normal placental tissues. The expression level of Keap1 in placenta of patients with PE was slightly lower than that of normal placenta. While the expression of Nrf2 in placenta of patients with PE was significantly higher than that of normal placenta. HO-1 expression in placenta of patients with PE was significantly higher than that of normal placenta. These results implicate the importance of Keap-1/Nrf2 pathway in PE.

[Adenosine deaminase as costimulatory molecule and marker of cellular immunity]. / Adenosin deaminasa como molécula coestimuladora y marcador de inmunidad celular.

Adenosine deaminase (ADA) is an enzyme of purine metabolism which has been the subject of much interest because the congenital defect of this enzyme causes severe combined immunodeficiency syndrome. One of the three isoforms of the enzyme (ecto-ADA) is capable of binding to the glycoprotein CD26 and adenosine receptors A1 and A2B. ADA-CD26 interaction produces a costimulatory signal in the events of T cell activation and secretion of IFN-gamma, TNF-alpha and IL-6. During this activation, the enzyme activity is regulated positively by IL-2 and IL-12 and negatively by IL-4, based on the mechanism of translocation. Diverse studies suggest that seric and plasmatic levels of ADA rise in some diseases caused by microorganisms infecting mainly the macrophages and in hypertensive disorders, which may represent a compensatory mechanism resulting from increased adenosine levels and the release of hormones and inflammatory mediators estimulated by hipoxia.

Examination of the expression of cyclooxygenase-2 in placenta villi from sufferers of pregnancy induced hypertension.

OBJECTIVES: The purpose of this paper is to elucidate the roles of phospholipase A(2) (PLA(2)), cyclooxygenase-2 (COX-2), and prostaglandin I(2) (PGI(2)) synthase in pregnancy induced hypertension (PIH). METHODS: In placentas from normal pregnant women and pregnant women with severe PIH, the enzyme expression of PLA(2), COX-2, and PGI(2) synthase was measured using real time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The expression of each enzyme was compared between normal (n=12) and PIH (n=12) groups. The expression levels of COX-2 and PGI(2) synthase during PIH pregnancy were significantly decreased to about 51% and 68%, respectively, of their values in normal pregnancy. However, the expression of PLA(2) was hardly changed by PIH. CONCLUSIONS: The decreases in COX-2 and PGI(2) synthase expression in severe PIH placentas may be causal factors in the disruption of the PGI(2)-thromboxane A(2) (TXA(2)) balance in favor of TXA(2). The decrease in COX-2 was more marked than that of PGI(2) synthase.

Adenosine deaminase activity in subjects with normal pregnancy, pregnancy induced hypertension and pre-eclampsia.

BACKGROUND: Both pregnancy and adenosine deaminase (ADA) are associated with depressed cellular mediated immunity. There is little information on ADA activity in pregnant Africans. OBJECTIVE: To determine the serum levels of adenosine deaminase (ADA) in normal pregnancy and pregnancy complicated by hypertension in Nigerian women. METHODS: One hundred and twenty-five pregnant women comprising 35 normal non-pregnant women, 35 normal pregnant women, 35 pregnant women with pregnancy induced hypertension and 20 patients with pre-eclampsia were recruited for the study. Serum adenosine deaminase enzyme (ADA) activity was measured by the Giusti and Galanti spectrophotometric method in all study subjects. RESULTS: The mean serum ADA level in the non-pregnant women was higher than that in the normal pregnant women (23.21 +/- 6.3 v 14.69 +/- 3.2, p<0.001). Amongst the pregnant women, mean serum ADA in the hypertensive and pre-eclamptic women was significantly higher than that in the normal pregnant group (p<0.001). CONCLUSION: These findings indicate a probable decrease in cellular immunity in normal pregnancy and an enhanced cell mediated immunity in pre-eclampsia.

Hypertension, augmented activity of matrix metalloproteinases-2 and -9 and angiogenic imbalance in hypertensive pregnancy are attenuated by doxycycline.

Preeclampsia is manifested as maternal hypertension and fetal growth restriction. Matrix metalloproteinases (MMPs) are involved in hypertension and doxycycline reduces blood pressure by inhibition of MMPs. Moreover, excessive levels of MMPs and reduced nitric oxide (NO) bioavailability have been related to preeclampsia. We investigated the involvement of MMPs in hypertension in pregnancy induced by Nω-Nitro-L-arginine methyl ester (L-NAME) in rats. To this end, zimography was performed to evaluate the activity of MMPs -2 and -9 in placenta, uterus and thoracic aorta, and systolic blood pressure, feto-placental development and metabolites of NO were evaluated. Also, plasma antioxidant capacity, plasma levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PLGF) were examined. Doxycycline prevented hypertensive pregnancy and significant reductions in number of pups induced by L-NAME. Low NO bioavailability was found in hypertensive pregnant rats treated (or not) with doxycycline. Increased activity of placental MMP-2 and MMP-9 and uterine MMP-2 were attenuated by doxycycline. MMP-2 activity of thoracic aorta showed no change after hypertension. Increases in PLGF with concomitant decreases in sFlt-1 levels were found with doxycycline treatment. Also, plasma antioxidant capacity was improved with doxycycline. Also, elevations of plasma antioxidant capacity were observed in hypertensive rats treated with doxycycline. Therefore, we suggest that L-NAME reduced NO and this triggered the increases in MMP-2 and -9 activities during hypertensive pregnancy. Importantly, increases in MMPs activation and angiogenic imbalance were attenuated by doxycycline and these effects were associated with decreases in systolic blood pressure.

[Markers of oxidative stress in pregnancies complicated by pregnancy induced hypertension and intrahepatic cholestasis]. / Niektóre wykladniki stresu oksydacyjnego w ciazy powiklanej nadcisnieniem tetniczym i cholestaza.

OBJECTIVE: The aim of the study was to investigate levels of superoxide dismutase (CuZnSOD-1), catalase (CAT), glutathione peroxidase (GPx) and malonodialdehyde (MDA) in groups of pregnant women with pregnancy induced hypertension (PIH), hypertension recognized before pregnancy (HA) or intrahepatic cholestasis. MATERIAL AND METHODS: 33 women with PIH, 6 with HA and 12 with cholestasis were compared with 33 healthy pregnant women. Levels of enzymes were assessed in blood samples. Methods of delivery and obstetric results were presented. RESULTS: SOD and GPx levels did not differ significantly in any of the investigated groups. A tendency for lower mean levels of CAT in the group of PIH women, and a higher level of MDA in the group of women with HA has been noted. The mean CAT level was significantly lower in PIH and HA patients delivered instantaneously due to the risk of eclampsia. All mean levels of enzymes in the group of women with cholestasis were similar to the ones in the group of healthy women. Patients with PIH and HA gave birth more often by cesarean section, but the overall condition of the newborns was satisfactory. CONCLUSIONS: There is no substantial evidence that the level of oxidative enzymes in a blood sample can be an indicator of oxidative stress in pregnant women with PIH, HA or cholestasis. Although CAT levels were lower in PIH and HA women who had cesarean section due to the risk of eclampsia, there was no correlation between these enzyme levels and the clinical outcome of patients or the condition of the newborns.

Role of Nitric Oxide Synthase on Blood Pressure Regulation and Vascular Function in Pregnant Rats on a High-Fat Diet.

BACKGROUND: While obesity is a leading risk factor for preeclampsia, the mechanisms whereby obese women are more susceptible to pregnancy-induced hypertension are unclear. As high-fat diet (HFD) is an important contributor to the development of obesity, we tested the hypothesis that pregnant rats on HFD have hypertension and endothelial dysfunction due to reduced nitric oxide synthase (NOS). METHODS: Twelve-week-old Sprague-Dawley female rats were fed normal diet (ND, 13% fat kcal) or HFD (40% fat kcal) for 9 weeks. Timed-pregnant rats were then generated and the effect of HFD on mean arterial blood pressure (MAP) and vascular function was assessed on gestational day (GD) 19. RESULTS: MAP was not different between HFD and ND pregnant rats. Intriguingly, sensitivity to acetylcholine-induced endothelium-dependent vasorelaxation was enhanced in small mesenteric arteries of HFD dams compared to ND controls (logEC50 -7.9 ± 0.3 vs. -6.7 ± 0.3 M; P < 0.05). Additionally, HFD dams exhibited higher mesenteric artery expression of NOS3 and plasma levels of NO metabolites than ND controls (1738.0 ± 316.4 vs. 1094.0 ± 82.5 pg/mg and 72.5 ± 8.7 vs. 39.7 ± 4.5 µM, respectively; both P < 0.05). Further, to determine the role of NOS in modulating blood pressure in HFD pregnant rats, animals were treated with the nonselective inhibitor Nω-Nitro-l-arginine methyl ester hydrochloride (100 mg/l, drinking water) from GD 14 to 19. It was found that NOS inhibition increased MAP equally in HFD and ND groups. CONCLUSIONS: Contrary to our initial hypothesis, HFD dams were normotensive and presented increased endothelial function and NO/NOS3 levels. This enhanced NOS-mediated vascular function does not appear to have a major impact on blood pressure regulation of HFD-fed pregnant rats.

Hydralazine is involved in tele-methylhistamine metabolism by inhibiting monoamine oxidase B in pregnancy-associated hypertensive mice.

Hypertensive disorders of pregnancy globally affect 6-8% of gestation and remain a major cause of both foetal and maternal morbidity and mortality. However, the antihypertensive medications for the patients of this disease are strictly limited due to the teratogenic potentials. Here, we found that tele-methylhistamine (tMH) increased in response to the administration of hydralazine (Hdz), a vasodilative agent, in the pregnancy-associated hypertensive (PAH) mice. Hdz abrogated the degradation of tMH catalyzed by monoamine oxidase B (MAO-B) in vitro. These results suggested that Hdz inhibited the MAO-B activity and consequently tMH increased in the maternal circulation of PAH mice.

A case of isolated peripartum elevation of alkaline phosphatase in pregnancy complicated by gestational diabetes.

Several isoenzymes of alkaline phosphatase are present in pregnancy, the most common are of liver, bone, and placental origin. We report a case of pregnancy complicated by hypertension and gestational diabetes, in which an extremely high elevation in bone isoenzyme was noted during labor. The enzyme level returned to normal by six weeks postpartum. Elevations in total serum alkaline phosphatase during pregnancy or labor cannot be assumed to arise from the placenta, and should be further investigated to determine the specific isoenzyme.

[Relationship between dopamine-beta-hydroxylase gene polymorphism and hypertensive disorder complicating pregnancy].

OBJECTIVE: To investigate the association between the single nucleotide polymorphism (SNP) at locus 589 of dopamine-beta-hydroxylase (DbetaH) gene and hypertensive disorder complicating pregnancy (HDCP). METHODS: One hundred and seven pregnant women with hypertensive disorder complicating pregnancy (HDCP group) and 95 normal pregnant women (control group) matched for age and gestation were selected. Genotypes of the SNP at locus 589 were typed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: (1) The frequencies of DbetaH GG, GA and AA genotypes of the SNP at locus 589 were 75.7%, 21.5% and 2.8% in HDCP group, respectively. They were 72.6%, 24.2% and 3.2% in normal control group, respectively (P > 0.05). The frequencies of the two alleles G and A were 86.4% and 13.6% in HDCP group, and 84.7% and 15.3% in normal control group, respectively (P > 0.05). (2) No evident differences existed in distribution of genotypes of the SNP at locus 589 between mild preeclampsia, severe preeclampsia and eclampsia groups (P > 0.05). CONCLUSION: The SNP at locus 589 of DbetaH gene is not associated with hypertensive disorder complicating pregnancy, nor is it associated with the severity of hypertensive disorder complicating pregnancy.

Sodium hydrosulfide prevents hypertension and increases in vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 in hypertensive pregnant rats.

Sodium hydrosulfide (NaHS) has presented antihypertensive and antioxidant effects and may reduce circulating soluble fms-like tyrosine kinase-1 (sFlt-1). We examined whether NaHS prevents maternal and fetal detrimental changes in a model of hypertension in pregnancy induced by N(G)-nitro-L-arginine methyl ester (L-NAME). Forty pregnant rats were divided into four groups (n = 10 per group): Norm-Preg, Preg + NaHS, HTN-Preg, or HTN-Preg + NaHS. Systolic blood pressure (SBP), number of viable fetuses, litter size, pups, and placentae weights were recorded. Circulating plasma sFlt-1, vascular endothelial growth factor (VEGF), myeloperoxidase (MPO), trolox equivalent antioxidant capacity (TEAC) levels, and biochemical determinants of nitric oxide (NO) formation were assessed. SBP values were elevated in the HTN-Preg group on gestational days 16, 18, and 20. However, HTN-Preg + NaHS group presented lower SBP values on days 18 and 20. Lower number of viable fetuses and litter size were found only in HTN-Preg group compared to other. Reductions in placental weight were found in HTN-Preg and HTN-Preg + NaHS groups. Increases in fetal weight were found only in Preg + NaHS group. Increases in circulating sFlt-1 and VEGF levels were observed only in HTN-Preg group compared to other. Higher MPO and lower TEAC plasma levels were found in HTN-Preg + NaHS and HTN-Preg groups. NO was diminished in HTN-Preg animals, and NaHS treatment increased NO levels only in hypertensive pregnant animals. Treatment with NaHS prevents hypertension in pregnancy and concomitantly reduces circulating plasma sFlt-1 and VEGF levels; this correlates with improved litter size with more viable fetuses and increase in NO levels. However, these beneficial effects presented no relation with oxidative stress.

Correlation of ACE gene deletion/insertion polymorphism and risk of pregnancy-induced hypertension: a meta-analysis based on 10,236 subjects.

OBJECTIVES: To clarify the association of angiotensin-converting enzyme (ACE) gene deletion/insertion polymorphism with risk of pregnancy-induced hypertension. METHODS: We systematically searched China National Knowledge Infrastructure, Wanfang database, Chongqing WeiPu database and PubMed up to March 2014 to collect related case-control studies. RevMan 5.0 software was used for meta-analysis after evaluating the quality of enrolled studies and extracting the data. RESULTS: A total of 45 case-control studies was selected, including 10,236 subjects. The meta-analysis was assessed by odds ratios (ORs) and 95% confidence intervals (CIs) after genotype consolidation. In total, D allele vs I allele: OR 1.57, 95% CI 1.33-1.86; genotype DD vs genotype II + DI: OR 1.86, 95% CI 1.48-2.32; genotype II vs genotype DI + DD: OR 0.65, 95% CI 0.53-0.80. In the Asian population, D allele vs I allele: OR 1.80, 95% CI 1.36-2.38; genotype DD vs genotype II + DI: OR 2.25, 95% CI 1.53-3.30; genotype II vs genotype DI + DD: OR 0.56, 95% CI 0.41-0.76. In the Caucasian population, D allele vs. I allele: OR 1.24, 95% CI 1.08-1.44; genotype DD vs. genotype II + DI: OR 1.25, 95% CI 1.10-1.41; genotype II vs. genotype DI + DD: OR 0.96, 95% CI 0.83-1.11. CONCLUSION: The ACE gene insertion/deletion polymorphism is associated with the risk of pregnancy-induced hypertension.