85 results on '"Kaitu'u-Lino, Tu'uhevaha"'
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2. Exploring the Therapeutic Potential of C-Type Natriuretic Peptide for Preeclampsia.
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Fato, Bianca R., de Alwis, Natasha, Beard, Sally, Binder, Natalie K., Pritchard, Natasha, Kaitu'u-Lino, Tu'uhevaha J., Bubb, Kristen J., and Hannan, Natalie J.
- Abstract
BACKGROUND: Preeclampsia is a serious condition of pregnancy, complicated by aberrant maternal vascular dysfunction. CNP (C-type natriuretic peptide) contributes to vascular homeostasis, acting through NPR-B (natriuretic peptide receptor-B) and NPR-C (natriuretic peptide receptor-C). CNP mitigates vascular dysfunction of arteries in nonpregnant cohorts; this study investigates whether CNP can dilate maternal arteries in ex vivo preeclampsia models. METHODS: Human omental arteries were dissected from fat biopsies collected during cesarean section. CNP, NPR-B, and NPR-C mRNA expression was assessed in arteries collected from pregnancies complicated by preeclampsia (n=6) and normotensive controls (n=11). Using wire myography, we investigated the effects of CNP on dilation of arteries from normotensive pregnancies. Arteries were preconstricted with either serum from patients with preeclampsia (n=6) or recombinant ET-1 (endothelin-1; vasoconstrictor elevated in preeclampsia; n=6) to model vasoconstriction associated with preeclampsia. Preconstricted arteries were treated with recombinant CNP (0.001-100 µmol/L) or vehicle and vascular relaxation assessed. In further studies, arteries were preincubated with NPR-B (5 µmol/L) and NPR-C (10 µmol/L) antagonists before serum-induced constriction (n=4-5) to explore mechanistic signaling. RESULTS: CNP, NPR-B, and NPR-C mRNAs were not differentially expressed in omental arteries from preeclamptic pregnancies. CNP potently stimulated maternal artery vasorelaxation in our model of preeclampsia (using preeclamptic serum). Its vasodilatory actions were driven through the activation of NPR-B predominantly; antagonism of this receptor alone dampened CNP vasorelaxation. Interestingly, CNP did not reduce ET-1--driven omental artery constriction. CONCLUSIONS: Collectively, these data suggest that enhancing CNP signaling through NPR-B offers a potential therapeutic strategy to reduce systemic vascular constriction in preeclampsia. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Circulating trace elements for the prediction of preeclampsia and small for gestational age babies
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McKeating, Daniel R., Fisher, Joshua J., MacDonald, Teresa, Walker, Sue, Tong, Stephen, Bennett, William W., Kaitu’u-Lino, Tu’uhevaha J., and Perkins, Anthony V.
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- 2021
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4. Cell surface associated protein mucin 15 (MUC15) is elevated in preeclampsia.
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Nguyen, Anna, Cannon, Ping, Kandel, Manju, Nguyen, Tuong-Vi, Baird, Lydia, Wong, Georgia, Hannan, Natalie J., Tong, Stephen, Bartho, Lucy, and Kaitu'u-Lino, Tu'uhevaha J.
- Abstract
Mucins are a family of proteins that protect the epithelium. A particular type of mucin, MUC15 is highly expressed in the placenta. This study aimed to characterise MUC15 in preeclampsia and investigate its role in placental stem cell biology. MUC15 mRNA and protein were measured in placentas from patients with early onset (<34 weeks' gestation) preeclampsia. Circulating serum MUC15 was measured via ELISA. MUC15 was localised in the placenta using in situ hybridisation. MUC1 5 mRNA expression was measured across differentiation of human trophoblast stem cells (hTSCs) to syncytiotrophoblast and extravillous trophoblasts. MUC15 was measured after syncytialised hTSCs were cultured in hypoxic (1% O 2) and proinflammatory (TNF α , IL-6) conditions. MUC15 secretion was assessed when syncytialised hTSCs were treated with brefeldin A (impairs protein trafficking) and batimastat (inhibits matrix metalloproteinases). MUC15 protein was significantly increased in the placenta (P = 0.0003, n = 32 vs n = 20 controls) and serum (P = 0.016, n = 32 vs n = 22 controls) of patients with preeclampsia, whilst MUC1 5 mRNA remained unchanged (n = 61 vs n = 18 controls). MUC1 5 mRNA (P = 0.005) and protein secretion (P = 0.006) increased following differentiation to syncytiotrophoblast cells. In situ hybridisation confirmed MUC15 localised to the syncytiotrophoblast cell within the placenta. Neither hypoxic or inflammatory conditions changed MUC1 5 mRNA expression or secretion. Brefeldin A treated hTSCs did not alter MUC15 secretion, whilst batimastat reduced MUC15 secretion (P = 0.044). MUC15 is increased in early onset preeclampsia and is cleaved by matrix metalloproteinases. Increased MUC15 may reflect a protective mechanism associated with placental dysfunction. Further research will aid in confirming this. • MUC15 was increased in the placenta and circulation of patients with preeclampsia. • MUC15 was localised to the syncytiotrophoblast cell layer of the placenta. • Matrix metalloproteinases may be involved in the cleavage of MUC15. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Epidermal Growth Factor Rescues Endothelial Dysfunction in Primary Human Tissues In Vitro
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Hastie, Roxanne, Tong, Stephen, Hannan, Natalie J., Brownfoot, Fiona, Cannon, Ping, and Kaitu’u-Lino, Tu’uhevaha J.
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- 2017
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6. Quantitative Point of Care Tests for Timely Diagnosis of Early‐Onset Preeclampsia with High Sensitivity and Specificity.
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Masoumeh Ghorbanpour, Sahar, Wen, Shihui, Kaitu'u‐Lino, Tu'uhevaha J, Hannan, Natalie J., Jin, Dayong, and McClements, Lana
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PREECLAMPSIA ,POINT-of-care testing ,SENSITIVITY & specificity (Statistics) ,CARDIOVASCULAR diseases ,DIAGNOSIS ,CD44 antigen - Abstract
Preeclampsia is a heterogeneous and multiorgan cardiovascular disorder of pregnancy. Here, we report the development of a novel strip‐based lateral flow assay (LFA) using lanthanide‐doped upconversion nanoparticles conjugated to antibodies targeting two different biomarkers for detection of preeclampsia. We first measured circulating plasma FKBPL and CD44 protein concentrations from individuals with early‐onset preeclampsia (EOPE), using ELISA. We confirmed that the CD44/FKBPL ratio is reduced in EOPE with a good diagnostic potential. Using our rapid LFA prototypes, we achieved an improved lower limit of detection: 10 pg ml−1 for FKBPL and 15 pg ml−1 for CD44, which is more than one order lower than the standard ELISA method. Using clinical samples, a cut‐off value of 1.24 for CD44/FKBPL ratio provided positive predictive value of 100 % and the negative predictive value of 91 %. Our LFA shows promise as a rapid and highly sensitive point‐of‐care test for preeclampsia. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Circulating Chemerin Is Elevated in Women With Preeclampsia.
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Bartho, Lucy A, Kandel, Manju, Walker, Susan P, Cluver, Catherine A, Hastie, Roxanne, Bergman, Lina, Pritchard, Natasha, Cannon, Ping, Nguyen, Tuong-Vi, Wong, Georgia P, MacDonald, Teresa M, Keenan, Emerson, Hannan, Natalie J, Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha J
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PREECLAMPSIA ,PREGNANT women ,TROPHOBLAST - Abstract
Background: Preeclampsia is a severe complication of pregnancy. Chemerin is an adipokine secreted from adipose tissue and highly expressed in placenta. This study evaluated the biomarker potential of circulating chemerin to predict preeclampsia. Methods: Maternal plasma and placenta were collected from women with early-onset preeclampsia (<34 weeks), with preeclampsia and eclampsia, or before preeclampsia diagnosis (36 weeks). Human trophoblast stem cells were differentiated into syncytiotrophoblast or extravillous trophoblasts across 96 hours. Cells were cultured in 1% O
2 (hypoxia) or 5% O2 (normoxia). Chemerin was measured by enzyme-linked immunosorbent assay (ELISA) and RARRES2 (gene coding chemerin) by reverse transcription-quantitative polymerase chain reaction. Results: Circulating chemerin was increased in 46 women with early-onset preeclampsia (<34 weeks) compared to 17 controls (P <.0006). Chemerin was increased in placenta from 43 women with early-onset preeclampsia compared to 24 controls (P <.0001). RARRES2 was reduced in placenta from 43 women with early-onset preeclampsia vs 24 controls (P <.0001). Chemerin was increased in plasma from 26 women with established preeclampsia (P =.006), vs 15 controls. Circulating chemerin was increased in 23 women who later developed preeclampsia vs 182 who did not (P = 3.23 × 10−6 ). RARRES2 was reduced in syncytiotrophoblast (P =.005) or extravillous trophoblasts (P <.0001). Hypoxia increased RARRES2 expression in syncytiotrophoblast (P =.01) but not cytotrophoblast cells. Conclusions: Circulating chemerin was elevated in women with early-onset preeclampsia, established preeclampsia, and preceding preeclampsia diagnosis of preeclampsia. RARRES2 was dysregulated in placenta complicated by preeclampsia and may be regulated through hypoxia. Chemerin may have potential as a biomarker for preeclampsia but would need to be combined with other biomarkers. [ABSTRACT FROM AUTHOR]- Published
- 2023
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8. Investigating the Effects of Atrial Natriuretic Peptide on the Maternal Endothelium to Determine Potential Implications for Preeclampsia.
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Binder, Natalie K., Beard, Sally, de Alwis, Natasha, Fato, Bianca R., Nguyen, Tuong-Vi, Kaitu'u-Lino, Tu'uhevaha J., and Hannan, Natalie J.
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ATRIAL natriuretic peptides ,PREECLAMPSIA ,ENDOTHELIUM ,ENDOTHELIUM diseases ,ENDOTHELIAL cells ,CARDIOVASCULAR diseases - Abstract
Preeclampsia is associated with an increased lifelong risk of cardiovascular disease (CVD). It is not clear whether this is induced by persistent systemic organ and vascular damage following preeclampsia or due to a predisposition to both conditions that share cardiovascular pathophysiology. Common to both CVD and preeclampsia is the dysregulation of corin and its proteolytic product, atrial natriuretic peptide (ANP). ANP, a hypotensive hormone converted from pro-ANP by corin, is involved in blood pressure homeostasis. While corin is predominantly a cardiac enzyme, both corin and pro-ANP are significantly upregulated in the gravid uterus and dysregulated in preeclampsia. Relatively little is known about ANP function in the endothelium during a pregnancy complicated by preeclampsia. Here, we investigated the effect of ANP on endothelial cell proliferation and migration, markers of endothelial dysfunction, and receptor expression in omental arteries exposed to circulating preeclamptic toxins. ANP receptor expression is significantly upregulated in preeclamptic vasculature but not because of exposure to preeclampsia toxins tumour necrosis factor α or soluble fms-like tyrosine kinase-1. The supplementation of endothelial cells with ANP did not promote proliferation or migration, nor did ANP improve markers of endothelial dysfunction. The role of ANP in preeclampsia is unlikely to be via endothelial pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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9. Assessing the sensitivity of placental growth factor and soluble fms-like tyrosine kinase 1 at 36 weeks’ gestation to predict small-for-gestational-age infants or late-onset preeclampsia: a prospective nested case-control study
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MacDonald, Teresa M., Tran, Chuong, Kaitu’u-Lino, Tu’uhevaha J., Brennecke, Shaun P., Hiscock, Richard J., Hui, Lisa, Dane, Kirsten M., Middleton, Anna L., Cannon, Ping, Walker, Susan P., and Tong, Stephen
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- 2018
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10. Expression of Myostatin in Intrauterine Growth Restriction and Preeclampsia Complicated Pregnancies and Alterations to Cytokine Production by First-Trimester Placental Explants Following Myostatin Treatment
- Author
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Peiris, Hassendrini. N., Georgiou, Harry, Lappas, Martha, Kaitu’u-Lino, Tu’uhevaha, Salomón, Carlos, Vaswani, Kanchan, Rice, Gregory. E., and Mitchell, Murray D.
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- 2015
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11. Sulfasalazine for the treatment of preeclampsia in a nitric oxide synthase antagonist mouse model.
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Binder, Natalie K., de Alwis, Natasha, Beard, Sally, Kadife, Elif, Harper, Alesia, Kaitu'u-Lino, Tu'uhevaha J., Brownfoot, Fiona C., and Hannan, Natalie J.
- Abstract
Development of a therapeutic that targets the pathophysiological elements of preeclampsia would be a major advance for obstetrics, with potential to save the lives of countless mothers and babies. We recently identified anti-inflammatory drug sulfasalazine as a prospective candidate therapeutic for treatment of preeclampsia. In primary human cells and tissues in vitro , sulfasalazine potently decreased secretion of anti-angiogenic sFlt-1 and sENG, increased production of pro-angiogenic PlGF, mitigated endothelial dysfunction, and promoted whole vessel vasodilation. Using nitric oxide synthase antagonist Nω-Nitro- l -arginine methyl ester hydrochloride, a preeclampsia-like phenotype was induced in pregnant mice, including high blood pressure, fetal growth restriction, and elevated circulating sFlt-1. Mice were treated with sulfasalazine or vehicle from gestational day (D)13.5, with blood pressure measurements across gestation, fetal measurements at D17.5, and wire myograph assessment of vasoactivity. Sulfasalazine had a modest effect on blood pressure, decreasing diastolic and mean blood pressure on D13.5, but not later in gestation, or systolic blood pressure. Sulfasalazine was not able to rescue fetal growth, in male or female fetuses. There was a suggestion of improved vasoactivity with sulfasalazine, but further clarification is required. In this mouse model of preeclampsia, sulfasalazine did not sustain reductions in blood pressure nor affect fetal parameters of size and weight, both desirable attributes of a viable preeclampsia therapeutic. While these data suggest sulfasalazine might improve vasoactivity, murine toxicity considerations limited the dose range of sulfasalazine that could be tested in the current study. • Sulfasalazine modestly decreases blood pressure in a mouse model of preeclampsia. • Sulfasalazine was unable to rescue fetal growth restriction. • Sulfasalazine may improve vasoactivity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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12. Placental DAAM2 is unaltered in preeclampsia, but upregulated by treatment with proton pump inhibitors.
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de Alwis, Natasha, Beard, Sally, Binder, Natalie K., Pritchard, Natasha, Tong, Stephen, Kaitu'u-Lino, Tu'uhevaha J., and Hannan, Natalie J.
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Background: Dishevelled Associated Activator Of Morphogenesis 2 (DAAM2) levels are elevated in the maternal circulation and placenta in pregnancies complicated by fetal growth restriction. However, placental DAAM2 levels in cases of preeclampsia have not previously been explored. Here, we examined placental DAAM2 in pregnancies complicated by preterm preeclampsia, and whether candidate preeclampsia therapeutics altered its expression.Methods: DAAM2 mRNA and protein levels were assessed in placental tissue from cases of preterm preeclampsia and gestation-matched controls (delivering ≤ 34 weeks; qPCR and western blot respectively). Short interfering RNAs were used to silence DAAM2 in isolated primary cytotrophoblast under normoxic (8 % O2) and hypoxic (1 % O2) conditions, and expression of anti-angiogenic sFLT-1, angiogenic PGF, antioxidant, fetal growth, and inflammatory genes assessed. DAAM2 expression was measured in placental explant tissue from pregnancies complicated by preeclampsia, treated with three proton pump inhibitors (100 µM esomeprazole, lansoprazole, and rabeprazole).Results: DAAM2 expression was significantly reduced in preeclamptic placental tissue compared to controls, but protein production was unchanged. Silencing DAAM2 in hypoxic cytotrophoblast increased sFLT-i13 isoform expression, but did not alter sFLT-e15a or PGF expression, or sFLT-1 secretion. DAAM2 knockdown did not alter expression of antioxidant (NQO-1, TXN, GCLC), fetal growth (SPINT1), or inflammasome (NLRP3) genes. Esomeprazole and lansoprazole, but not rabeprazole, increased DAAM2 expression in placental explant tissue from cases of preeclampsia.Conclusion: Placental DAAM2 protein is not significantly altered in placental tissue in cases of preeclampsia, and its suppression does not alter sFLT-1 secretion. Hence, placental DAAM2 is unlikely to drive the pathogenesis associated with preeclampsia. [ABSTRACT FROM AUTHOR]- Published
- 2022
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13. Placental galectin-3 is reduced in early-onset preeclampsia.
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Kandel, Manju, Tong, Stephen, Walker, Susan P., Cannon, Ping, Nguyen, Tuong-Vi, MacDonald, Teresa M., Hannan, Natalie J., Kaitu'u-Lino, Tu'uhevaha J., and Bartho, Lucy A.
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GALECTINS ,PREECLAMPSIA ,PREGNANCY proteins ,BLOOD proteins ,CARRIER proteins - Abstract
Preeclampsia is a disease of pregnancy responsible for significant maternal and neonatal mortality. Galectin-3 is a β-Galactoside binding protein. This study aimed to characterise galectin-3 in women with preeclampsia and human trophoblast stem cells (hTSCs). Galectin-3 was measured in placental lysates and plasma collected from patients with early-onset preeclampsia (delivered <34 weeks' gestation) and gestation matched controls. Placental galectin-3 protein was significantly reduced in 43 women with early-onset preeclampsia compared to 21 controls. mRNA expression of LGALS3 (galectin-3 encoding gene) was reduced in 29 women with early-onset preeclampsia, compared to 18 controls (p = 0.009). There was no significant difference in plasma galectin-3 protein in 46 women with early-onset preeclampsia compared to 20 controls. In a separate cohort of samples collected at 36 weeks' gestation, circulating galectin-3 was not altered in 23 women who later developed preeclampsia, versus 182 who did not. In syncytialised hTSCs, hypoxia increased mRNA expression of LGALS3 (p = 0.01). Treatment with inflammatory cytokines (TNF-α and IL-6) had no effect on LGALS3 mRNA expression. However, TNF-α treatment caused an increase in mRNA expression of LGALS3BP (galectin-3 binding protein encoding gene) in hTSCs (p = 0.03). This study showed a reduction of galectin-3 in placenta from pregnancies complicated by early-onset preeclampsia. LGALS3 mRNA expression was dysregulated by hypoxia exposure in placental stem cells. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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14. Serum Collected from Preeclamptic Pregnancies Drives Vasoconstriction of Human Omental Arteries—A Novel Ex Vivo Model of Preeclampsia for Therapeutic Development.
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Fato, Bianca R., de Alwis, Natasha, Beard, Sally, Binder, Natalie K., Pritchard, Natasha, Tong, Stephen, Kaitu'u-Lino, Tu'uhevaha J., and Hannan, Natalie J.
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PREECLAMPSIA ,VASOCONSTRICTION ,ENDOTHELIUM diseases ,ARTERIES ,PREGNANCY ,CESAREAN section - Abstract
New-onset maternal hypertension is a hallmark of preeclampsia, driven by widespread endothelial dysfunction and systemic vasoconstriction. Here, we set out to create a new ex vivo model using preeclamptic serum to cause injury to the endothelium, mimicking vascular dysfunction in preeclampsia and offering the potential to evaluate candidate therapeutic interventions. Human omental arteries were collected at caesarean section from normotensive pregnant patients at term (n = 9). Serum was collected from pregnancies complicated by preterm preeclampsia (birth < 34 weeks' gestation, n = 16), term preeclampsia (birth > 37 weeks' gestation, n = 5), and healthy gestation-matched controls (preterm n = 16, term n = 12). Using wire myography, we performed ex vivo whole vessel assessment where human omental arteries were treated with increasing doses of each serum treatment (2–20%) and vasoreactivity was assessed. All pregnant serum treatments successfully drove vasoconstriction; no significant difference was observed in the degree of vasoconstriction when exposed to preeclamptic or control serum. We further demonstrated the ability of esomeprazole (a candidate therapeutic for preeclampsia; 0.1–100 µM) to drive vasorelaxation of pre-constricted vessels (only with serum from preeclamptic patients). In summary, we describe a novel human physiological model of preeclamptic vascular constriction. We demonstrate its exciting potential to screen drugs for their therapeutic potential as treatment for vasoconstriction induced by preeclampsia. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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15. Assessment of the Proton Pump Inhibitor, Esomeprazole Magnesium Hydrate and Trihydrate, on Pathophysiological Markers of Preeclampsia in Preclinical Human Models of Disease.
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de Alwis, Natasha, Fato, Bianca R., Beard, Sally, Binder, Natalie K., Kaitu'u-Lino, Tu'uhevaha J., Onda, Kenji, and Hannan, Natalie J.
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PREECLAMPSIA ,PROTON pump inhibitors ,ESOMEPRAZOLE ,VASCULAR cell adhesion molecule-1 ,ANIMAL models in research ,REACTIVE oxygen species - Abstract
Previously, we demonstrated that the proton pump inhibitor, esomeprazole magnesium hydrate (MH), could have potential as a repurposed treatment against preeclampsia, a serious obstetric condition. In this study we investigate the difference in the preclinical effectiveness between 100 µM of esomeprazole MH and its hydration isomer, esomeprazole magnesium trihydrate (MTH). Here, we found that both treatments reduced secretion of sFLT-1 (anti-angiogenic factor) from primary cytotrophoblast, but only esomeprazole MH reduced sFLT-1 secretion from primary human umbilical vein endothelial cells (assessed via ELISA). Both drugs could mitigate expression of the endothelial dysfunction markers, vascular cell adhesion molecule-1 and endothelin-1 (via qPCR). Neither esomeprazole MH nor MTH quenched cytotrophoblast reactive oxygen species production in response to sodium azide (ROS assay). Finally, using wire myography, we demonstrated that both compounds were able to induce vasodilation of human omental arteries at 100 µM. Esomeprazole is safe to use in pregnancy and a candidate treatment for preeclampsia. Using primary human tissues and cells, we validated that esomeprazole is effective in enhancing vascular relaxation, and can reduce key factors associated with preeclampsia, including sFLT-1 and endothelial dysfunction. However, esomeprazole MH was more efficacious than esomeprazole MTH in our in vitro studies. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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16. Placental OLAH Levels Are Altered in Fetal Growth Restriction, Preeclampsia and Models of Placental Dysfunction.
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de Alwis, Natasha, Beard, Sally, Binder, Natalie K., Pritchard, Natasha, Kaitu'u-Lino, Tu'uhevaha J., Walker, Susan P., Stock, Owen, Groom, Katie, Petersen, Scott, Henry, Amanda, Said, Joanne M., Seeho, Sean, Kane, Stefan C., Tong, Stephen, Hui, Lisa, and Hannan, Natalie J.
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PLACENTA ,TROPHOBLAST ,PREECLAMPSIA ,FETAL growth retardation ,PREGNANCY proteins ,GENE expression - Abstract
Previously, we identified elevated transcripts for the gene Oleoyl-ACP Hydrolase (OLAH) in the maternal circulation of pregnancies complicated by preterm fetal growth restriction. As placental dysfunction is central to the pathogenesis of both fetal growth restriction and preeclampsia, we aimed to investigate OLAH levels and function in the human placenta. We assessed OLAH mRNA expression (qPCR) throughout pregnancy, finding placental expression increased as gestation progressed. OLAH mRNA and protein levels (Western blot) were elevated in placental tissue from cases of preterm preeclampsia, while OLAH protein levels in placenta from growth-restricted pregnancies were comparatively reduced in the preeclamptic cohort. OLAH expression was also elevated in placental explant tissue, but not isolated primary cytotrophoblast cultured under hypoxic conditions (as models of placental dysfunction). Further, we discovered that silencing cytotrophoblast OLAH reduced the expression of pro- and anti-apoptosis genes, BAX and BCL2, placental growth gene, IGF2, and oxidative stress gene, NOX4. Collectively, these findings suggest OLAH could play a role in placental dysfunction and may be a therapeutic target for mitigating diseases associated with this vital organ. Further research is required to establish the role of OLAH in the placenta, and whether these changes may be a maternal adaptation or consequence of disease. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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17. Actions of Esomeprazole on the Maternal Vasculature in Lean and Obese Pregnant Mice with Impaired Nitric Oxide Synthesis: A Model of Preeclampsia.
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de Alwis, Natasha, Binder, Natalie K., Mangwiro, Yeukai T. M., Beard, Sally, Pritchard, Natasha, Kadife, Elif, Fato, Bianca R., Keenan, Emerson, Brownfoot, Fiona C., Kaitu'u-Lino, Tu'uhevaha J., and Hannan, Natalie J.
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PREECLAMPSIA ,NITRIC oxide ,ESOMEPRAZOLE ,NITRIC-oxide synthases ,BLOOD pressure ,PROTON pump inhibitors - Abstract
Preeclampsia is a devastating, multisystem disorder of pregnancy. It has no cure except delivery, which if premature can impart significant neonatal morbidity. Efforts to repurpose pregnancy-safe therapeutics for the treatment of preeclampsia have led to the assessment of the proton pump inhibitor, esomeprazole. Preclinically, esomeprazole reduced placental secretion of anti-angiogenic sFlt-1, improved endothelial dysfunction, promoted vasorelaxation, and reduced maternal hypertension in a mouse model. Our understanding of the precise mechanisms through which esomeprazole works to reduce endothelial dysfunction and enhance vasoreactivity is limited. Evidence from earlier studies suggested esomeprazole might work via the nitric oxide pathway, upregulating endothelial nitric oxide synthase (eNOS). Here, we investigated the effect of esomeprazole in a mouse model of L-NAME-induced hypertension (decreased eNOS activity). We further antagonised the model by addition of diet-induced obesity, which is relevant to both preeclampsia and the nitric oxide pathway. Esomeprazole did not decrease blood pressure in this model, nor were there any alterations in vasoreactivity or changes in foetal outcomes in lean mice. We observed similar findings in the obese mouse cohort, except esomeprazole treatment enhanced ex vivo acetylcholine-induced vasorelaxation. As acetylcholine induces nitric oxide production, these findings hint at a function for esomeprazole in the nitric oxide pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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18. Circulating Activin A is elevated at 36 weeks' gestation preceding a diagnosis of preeclampsia.
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Wong, Georgia P., Andres, Faith, Walker, Susan P., MacDonald, Teresa M., Cannon, Ping, Nguyen, Tuong-Vi, Keenan, Emerson, Hannan, Natalie J., Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha J.
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PREECLAMPSIA diagnosis ,THIRD trimester of pregnancy ,CASE-control method ,PREECLAMPSIA ,PLACENTA ,PEPTIDE hormones ,LONGITUDINAL method - Abstract
Activin A is aberrantly expressed by the preeclamptic placenta and circulating levels have been investigated as a potential biomarker for the disease. In a nested case-control study we measured Activin A levels in maternal plasma at 28- and 36-weeks' gestation preceding term preeclampsia diagnosis. At 28 weeks Activin A was not significantly altered (n = 73 destined to develop preeclampsia vs n = 191 controls). At 36 weeks' gestation Activin A was significantly increased in 40 women destined to develop preeclampsia relative to 201 controls (p < 0.0001). These findings provide further validation of Activin A as a potential biomarker for subsequent term preeclampsia. [ABSTRACT FROM AUTHOR]
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- 2022
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19. Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia.
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Tong, Stephen, Kaitu'u-Lino, Tu'uhevaha J., Hastie, Roxanne, Brownfoot, Fiona, Cluver, Catherine, and Hannan, Natalie
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PLACENTAL growth factor ,ECULIZUMAB ,PREECLAMPSIA ,CLINICAL trials ,PRAVASTATIN ,TUMOR necrosis factors ,ANTITHROMBIN III - Abstract
There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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20. A disintegrin and metalloproteinase 12 (ADAM12) is reduced at 36 weeks' gestation in pregnancies destined to deliver small for gestational age infants.
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Andres, Faith, Wong, Georgia P., Walker, Susan P., MacDonald, Teresa M., Keenan, Emerson, Cannon, Ping, Nguyen, Tuong-Vi, Hannan, Natalie J., Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha J.
- Abstract
First trimester circulating ADAM12 is reduced in fetal growth restriction (FGR) and preeclampsia. We measured plasma ADAM12 at 36 weeks' gestation preceding diagnosis of term preeclampsia or delivery of a small for gestational age (SGA; birthweight <10th centile) infant in two independent cohorts (Cohort 1 90 SGA, 41 preeclampsia, 862 controls; Cohort 2121 SGA 23 preeclampsia; 190 controls). ADAM12 was reduced with SGA in both cohorts (p = 0.0015 and 0.011 respectively), and further reduced with birthweight <5th centile (p = 0.0013 and 0.0058 respectively). This validates ADAM12 as an SGA biomarker near term. Circulating ADAM12 preceding preeclampsia was not consistently altered. [ABSTRACT FROM AUTHOR]
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- 2022
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21. NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast.
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de Alwis, Natasha, Beard, Sally, Binder, Natalie K., Pritchard, Natasha, Kaitu'u-Lino, Tu'uhevaha J., Walker, Susan P., Stock, Owen, Groom, Katie M., Petersen, Scott, Henry, Amanda, Said, Joanne M., Seeho, Sean, Kane, Stefan C., Tong, Stephen, and Hannan, Natalie J.
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GENE expression ,PLACENTAL growth factor ,PREECLAMPSIA ,FETAL growth retardation ,PLACENTA ,PROTEIN expression - Abstract
Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O
2 compared to 8% O2 ) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2. [ABSTRACT FROM AUTHOR]- Published
- 2021
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22. Placental growth factor is negatively regulated by epidermal growth factor receptor (EGFR) signaling.
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Whigham, Carole-Anne, Hastie, Roxanne, Hannan, Natalie J., Brownfoot, Fiona, Pritchard, Natasha, Cannon, Ping, Nguyen, Tuong Vi, Kandel, Manju, Masci, Joshua, Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha J.
- Abstract
Introduction: Preeclampsia is associated with reduced pro-angiogenic Placental Growth Factor (PlGF) and increased levels of anti-angiogenic soluble FMS like tyrosine kinase-1 (sFlt-1). We have previously shown that sFlt-1 secretion is positively regulated via the Epidermal Growth Factor Receptor (EGFR) and mitochondrial respiration pathways. We assessed whether these pathways also regulate endothelial and placental secretion of PlGF.Methods: Primary cytotrophoblast cells and primary human umbilical vein endothelial cells (HUVECs) were treated with EGFR inhibitor gefitinib, or small molecules that inhibit down-stream pathways of the receptor: U0126, PD98059 (ERK/MEK pathway inhibitors), ZM336372 (JAK/STAT inhibitor) or AG490 (JAK inhibitor). We inhibited mitochondrial respiration in primary cytotrophoblasts using mitochondrial complex inhibitors rotenone (complex I), antimycin (complex III) or oligomycin (complex IV). We then measured PlGF secretion in the condition media.Results: Three inhibitors of the EGFR pathway significantly increased PlGF secretion: gefitinib (p = 0.03), AG490 (p < 0.0001) and U0126 (p = 0.03) in primary cytotrophoblasts, while PD98059 reduced PlGF secretion (p = 0.002). In the same cells, neither gefitinib or UO126 altered PlGF mRNA expression, but AG490 significantly increased its expression (p = 0.02). Primary endothelial cell PlGF secretion was significantly reduced when treated with PD98059 and U0126 while ZM336372 had no effect. Rotenone significantly reduced cytotrophoblast PlGF secretion (p = 0.0005). Neither antimycin (p = 0.9) or oligomycin (p = 0.9) had an effect.Discussion: We have shown that PlGF secretion from primary cytotrophoblast and HUVECs is altered by inhibiting EGFR signaling and potentially mitochondrial respiration, coincident with reduced sFlt-1 secretion. This suggests that common pathways are regulating both pro and anti-angiogenic molecules that are changed in association with preeclampsia and provides insight into the pathogenesis of this serious disease. [ABSTRACT FROM AUTHOR]- Published
- 2021
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23. LOX-1 expression is reduced in placenta from pregnancies complicated by preeclampsia and in hypoxic cytotrophoblast.
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de Alwis, Natasha, Beard, Sally, Binder, Natalie K., Pritchard, Natasha, Kaitu'u-Lino, Tu'uhevaha J., Walker, Susan P., Stock, Owen, Groom, Katie M., Petersen, Scott, Henry, Amanda, Said, Joanne M., Seeho, Sean, Kane, Stefan C., Tong, Stephen, and Hannan, Natalie J.
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BLASTOCYST ,PRENATAL diagnosis ,CELL receptors ,PREECLAMPSIA ,PLACENTA - Abstract
Objectives: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is upregulated in the maternal vasculature in preeclampsia, and contributes to oxidative stress and endothelial dysfunction. However, its function in the placenta is unclear. This paper investigated LOX-1 expression in models of placental dysfunction and preeclampsia, and whether candidate therapeutics for preeclampsia could alter its expression.Study Design: Placentas were collected from preterm pregnancies and cases of preterm preeclampsia and fetal growth restriction. Blood was collected from participants whose pregnancies were complicated by preterm fetal growth restriction and/or preeclampsia. Primary cytotrophoblast and placental explant tissue were cultured under hypoxic (1% O2) or normoxic (8% O2) conditions. Cytotrophoblast were exposed to 10% preeclamptic or control serum. Cytotrophoblast and preeclamptic explant tissue were treated with 100 µM esomeprazole, lansoprazole or rabeprazole.Main Outcome Measures: LOX-1 expression was assessed in all samples via qPCR.Results: LOX-1 expression was reduced in placentas from cases of preterm preeclampsia, but not fetal growth restriction, compared to controls. LOX-1 expression was reduced in cytotrophoblast under hypoxia, but not in explant tissue. Treatment with preeclamptic serum in vitro did not alter cytotrophoblast LOX-1 expression. Circulating LOX-1 mRNA was unaltered in patients with fetal growth restriction, preeclampsia, and fetal hypoxia, compared to controls. Treatment with esomeprazole or lansoprazole in vitro increased placental LOX-1 expression.Conclusions: LOX-1 expression is reduced in preeclamptic placentas and hypoxic cytotrophoblast. Esomeprazole and lansoprazole increase placental LOX-1 expression. These findings demonstrate a role for LOX-1 in the placenta, and improve our understanding of maternal adaptations in pregnancy complications. [ABSTRACT FROM AUTHOR]- Published
- 2021
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24. Circulating Tissue Factor Pathway Inhibitor (TFPI) is increased preceding preeclampsia diagnosis and in established preeclampsia.
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MacDonald, Teresa M., Tong, Stephen, Myers, Jenny, Cannon, Ping, Nguyen, Tuong-Vi, Keenan, Emerson, Murray, Elizabeth, Harper, Alesia, Pritchard, Natasha, Hannan, Natalie J., Dane, Kirsten M., Middleton, Anna L., Kyritsis, Valerie P., Walker, Susan P., and Kaitu'u-Lino, Tu'uhevaha J.
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PREECLAMPSIA diagnosis ,LIPOPROTEINS ,RESEARCH ,RESEARCH methodology ,CASE-control method ,MEDICAL cooperation ,EVALUATION research ,PREECLAMPSIA ,COMPARATIVE studies ,PLACENTA - Abstract
Introduction: Tissue Factor Pathway Inhibitor (TFPI) is a part of the extrinsic coagulation pathway, and highly expressed in the placenta. We aimed to assess its potential as a preeclampsia biomarker.Methods: Maternal plasma was prospectively collected at 36 weeks' gestation. Circulating TFPI was measured in a nested case-control group (39 women who developed preeclampsia, 98 controls), before being measured in a larger independent cohort along with Placental Growth Factor (PlGF; 41 who developed preeclampsia, 954 controls). Circulating TFPI was then measured in women with underlying vascular disease, and also assessed in the plasma and placentas from women with preterm preeclampsia (delivered at <34 weeks).Results: Circulating TFPI was significantly increased in women destined to develop preeclampsia in the case-control study, a finding that validated in Cohort 2, with median TFPI in the preeclampsia group being 42.3 ng/ml (IQR 30-51 ng/ml) compared to 30 ng/ml (IQR 23.1-38.6 ng/ml) in controls (p < 0.0001). The area under the receiver operator characteristic curve (AUC) was 0.70. PlGF was significantly reduced in the preeclampsia group, and a ratio of TFPI/PlGF had an improved AUC of 0.78. In women with underlying vascular disease who were later diagnosed with early onset preeclampsia, circulating TFPI was significantly increased with a 0.29 (95% CI 0.13-0.44) increase in logTFPI (adjusted for gestation and hypertensive status). Circulating and placental TFPI were significantly increased in women with preterm preeclampsia.Discussion: Circulating TFPI is increased in women preceding diagnosis of preeclampsia (at 36 weeks) and in women with preterm disease. TFPI may beneficially contribute to a multi-marker blood test to predict preeclampsia. [ABSTRACT FROM AUTHOR]- Published
- 2021
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25. Novel approaches to combat preeclampsia: from new drugs to innovative delivery.
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de Alwis, Natasha, Binder, Natalie K., Beard, Sally, Kaitu'u-Lino, Tu'uhevaha J., Tong, Stephen, Brownfoot, Fiona, and Hannan, Natalie J.
- Abstract
Preeclampsia is a complex disease affecting 2-8% of pregnancies worldwide. It poses significant risk of maternal and perinatal morbidity and mortality. Despite the rising research interest to discover new therapeutic approaches to prevent and treat preeclampsia, options remain limited. Identifying the important pathological stages in the progression of this disease allows us to evaluate effective candidate therapeutics. Three important stages in the pathophysiology are: 1) placental hypoxia and oxidative stress, 2) excess release of anti-angiogenic and pro-inflammatory factors, and 3) widespread systemic endothelial dysfunction and vasoconstriction. Repurposing drugs already safe for use in pregnancy is an attractive option for discovery of novel therapeutics. There are many drugs currently being assessed to treat preeclampsia, including proton pump inhibitors (PPIs), metformin, statins, sulfasalazine, sofalcone, resveratrol, melatonin, and sildenafil citrate. These drugs show positive effects in preclinical studies, targeting placental and endothelial dysfunction. However, using novel therapeutics can raise safety concerns for the developing fetus. Therefore, innovative targeted delivery systems are being developed to safely administer these therapeutics directly to the placenta and/or endothelium. These include nanoparticle delivery systems, developed and used by the oncology field, now being adapted for obstetrics. This technology is currently being assessed in animal models and shows promise for treating preeclampsia. Combining effective therapeutics with targeted drug delivery could be the future of preeclampsia treatment. [ABSTRACT FROM AUTHOR]
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- 2020
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26. Esomeprazole and sulfasalazine in combination additively reduce sFlt-1 secretion and diminish endothelial dysfunction: potential for a combination treatment for preeclampsia.
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Binder, Natalie K., Brownfoot, Fiona C., Beard, Sally, Cannon, Ping, Nguyen, Tuong V., Tong, Stephen, Kaitu'u-Lino, Tu'uhevaha J., and Hannan, Natalie J.
- Abstract
Development and repurposing of therapies that show promise in the prevention or treatment of preeclampsia would be a major advance for the obstetrics field. We recently identified esomeprazole and sulfasalazine as potential candidates for the treatment of preeclampsia. Both reduce placental and endothelial secretion of sFlt-1 and sENG and mitigate endothelial dysfunction in vitro. Here we assessed whether esomeprazole and sulfasalazine in combination would additively attenuate the elevated release of anti-angiogenic factors and markers of endothelial dysfunction, key characteristics of preeclampsia. Primary placental tissue and cells, and primary endothelial cells were treated with esomeprazole and sulfasalazine alone and in combination. We assessed secretion of sFlt-1 and sENG and performed in vitro assays of endothelial dysfunction. Combining esomeprazole and sulfasalazine in lower concentrations caused an additive reduction in sFlt-1 secretion in primary cytotrophoblasts, placental explants and endothelial cells. No additive reduction was observed in sENG secretion when esomeprazole and sulfasalazine were combined. Together, esomeprazole and sulfasalazine additively reduced TNF-α-induced VCAM and ET-1 mRNA expression, and monocyte adhesion to endothelial cells. In conclusion, combining esomeprazole and sulfasalazine additively reduced secretion of sFlt-1 and markers of endothelial dysfunction. Combined administration of esomeprazole and sulfasalazine may provide a more effective treatment or prevention for preeclampsia compared to either as single agents. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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27. Aurora kinase mRNA expression is reduced with increasing gestational age and in severe early onset fetal growth restriction.
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Beard, Sally, Pritchard, Natasha, Binder, Natalie, Schindler, Karen, De Alwis, Natasha, Kaitu'u-Lino, Tu'uhevaha J., Tong, Stephen, and Hannan, Natalie J.
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RNA metabolism ,RESEARCH ,AGE distribution ,RESEARCH methodology ,GESTATIONAL age ,FETAL growth retardation ,CASE-control method ,RNA ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,PLACENTA ,GENES ,TRANSFERASES ,RESEARCH funding - Abstract
Introduction: Oxidative damage and biochemical ageing are implicated in placental dysfunction and potentially fetal death. Cellular senescence may play a role in the pathophysiology of fetal growth restriction (FGR) and preeclampsia (PE). Aurora kinases (AURKA, B and C) are important regulators of cellular division in mitosis and meiosis with implications in cellular senescence. We aimed to investigate whether aurora kinase expression is altered with placental dysfunction or placental ageing.Methods: Placenta and blood was obtained across gestation from pregnancies complicated by PE, FGR or both PE and FGR, as well as gestation-matched control samples. Expression of AURKA, B and C mRNA was examined using real time qPCR in both the placenta and maternal circulation.Results: Placental aurora kinase expression decreased as gestation progressed: AURKA and AURKB were significantly reduced at 37-40 weeks, whereas AURKC was significantly reduced at 34-37 weeks, when compared to <34 weeks. In the maternal circulation, the mRNA level of AURKB was significantly reduced at >40 weeks compared to <34 weeks gestation. A significant reduction in AURKC was seen in FGR pregnancies <34 weeks compared to gestation-matched controls.Conclusion: Placental AURK expression is reduced with increased gestation. Circulating AURKB mRNA reduces at >40 weeks gestation, when compared to <34 weeks. AURKC is significantly reduced in placentas from pregnancies complicated by severe early onset (<34 weeks) FGR compared with gestation-matched controls. The functional role of aurora kinase in the placenta and in gestational age warrants further investigation. [ABSTRACT FROM AUTHOR]- Published
- 2020
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28. Combining metformin and sulfasalazine additively reduces the secretion of antiangiogenic factors from the placenta: Implications for the treatment of preeclampsia.
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Brownfoot, Fiona C., Hastie, Roxanne, Hannan, Natalie J., Cannon, Ping, Nguyen, Tuong V., Tuohey, Laura, Cluver, Cathy, Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha J.
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RESEARCH ,COMBINATION drug therapy ,ENDOTHELINS ,RESEARCH methodology ,CELL receptors ,MEDICAL cooperation ,EVALUATION research ,PREECLAMPSIA ,COMPARATIVE studies ,PLACENTA ,METFORMIN ,VASCULAR endothelial growth factors ,SULFONAMIDES ,ANTIGENS ,PHARMACODYNAMICS - Abstract
Introduction: The antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are elevated in preeclampsia and have been implicated in its pathogenesis. We have previously demonstrated metformin and sulfasalazine independently reduce antiangiogenic factor secretion. Here we examined whether combining metformin and sulfasalazine may be more effective than either alone in reducing placental expression and secretion of antiangiogenic and angiogenic factors and the expression of markers of endothelial dysfunction.Methods: We performed functional experiments using primary human placenta to explore the effect of metformin and sulfasalazine, at lower doses than previously explored, individually and in combination, on sFlt-1 and sENG secretion and placental growth factor (PlGF) and vascular endothelial growth factor (VEGFα) expression. Using primary endothelial cells we induced dysfunction using cytokine tumor necrosis factor-α (TNF-α) and assessed the effect of low dose combination treatment on the expression of vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (a potent vasoconstrictor).Results: We demonstrated combination metformin and sulfasalazine was additive in reducing sFlt-1 secretion from cytotrophoblasts and placental explants. Combination treatment was also additive in reducing sENG secretion from placental explants. Furthermore, combination treatment increased cytotrophoblast VEGFα mRNA expression. Whilst combination treatment increased PlGF mRNA expression this was similar to treatment with sulfasalazine alone. Combination therapy reduced TNFα induced endothelin-1 mRNA expression however did not change VCAM expression.Discussion: Low dose combination metformin and sulfasalazine reduced cytotrophoblast sFlt-1 and sENG secretion, increased VEGFα expression and reduced TNFα induced endothelin-1 expression in primary endothelial cells. Combination therapy has potential to treat preeclampsia. [ABSTRACT FROM AUTHOR]- Published
- 2020
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29. Pravastatin as the statin of choice for reducing pre-eclampsia-associated endothelial dysfunction.
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de Alwis, Natasha, Beard, Sally, Mangwiro, Yeukai T., Binder, Natalie K., Kaitu'u-Lino, Tu'uhevaha J., Brownfoot, Fiona C., Tong, Stephen, and Hannan, Natalie J.
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PRAVASTATIN ,RESEARCH ,ENDOTHELIUM ,CELL culture ,ENDOTHELINS ,RESEARCH methodology ,CELL physiology ,CELL receptors ,EVALUATION research ,MEDICAL cooperation ,PREECLAMPSIA ,COMPARATIVE studies ,SIMVASTATIN ,EPITHELIAL cells ,ANTIGENS ,PHARMACODYNAMICS - Abstract
Objectives: There is avid interest in pravastatin as a therapeutic intervention for pre-eclampsia, however little is known on statin action on endothelial dysfunction. This study aimed to evaluate the ability of pravastatin, simvastatin and rosuvastatin to reduce pre-eclampsia-associated markers of endothelial dysfunction in human endothelial cells.Study Design: Primary human umbilical vein endothelial cells (HUVECs) and uterine microvascular cells (UtMVs) were isolated and treated with 0.2, 2, 20 and 200 µM pravastatin, simvastatin and rosuvastatin for 24 h, either with or without pre-treatment with TNF-α to induce endothelial dysfunction.Main Outcome Measures: Cell viability (MTS) assays were performed and cells were visually inspected. Expression of endothelial dysfunction markers, endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were assessed by qPCR (n=3). Intracellular VCAM-1 protein was examined by Western Blotting (n=5). ET-1 and soluble fms-like tyrosine kinase-1 (sFLT-1) protein secretion was assessed by ELISA in HUVEC conditioned media (n=3).Results: High doses of simvastatin and rosuvastatin significantly compromised HUVEC survival. 200 µM simvastatin significantly reduced UtMV survival. Abnormal cell structure was observed with these doses and thus were excluded from further analysis. The statins did not mitigate TNF-α induced ET-1 or VCAM-1 expression in either HUVECs or UtMVs, nor VCAM-1 protein expression in HUVECs. 0.2 µM pravastatin and simvastatin significantly reduced ET-1 and sFLT-1 protein secretion.Conclusions: Pravastatin significantly reduced secretion of both ET-1 and sFLT-1, key mediators of endothelial dysfunction. Importantly, pravastatin had no toxic effects, in contrast to rosuvastatin and simvastatin. This further supports selection of pravastatin for clinical applications to combat pre-eclampsia. [ABSTRACT FROM AUTHOR]- Published
- 2020
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30. Death associated protein kinase 1 (DAPK-1) is increased in preeclampsia.
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Yung, Cameron, MacDonald, Teresa M., Walker, Susan P., Cannon, Ping, Harper, Alesia, Pritchard, Natasha, Hannan, Natalie J., Kaitu'u-Lino, Tu'uhevaha J., and Tong, Stephen
- Abstract
Introduction: Death associated protein kinase-1 (DAPK-1) is highly expressed in the placenta relative to all other human tissues. We examine whether it is differentially expressed with preeclampsia.Methods: We examined samples from a large prospective collection of plasma from 2002 women. We split the samples into two cohorts: Cohort 1 (n = 1000) and Cohort 2 (n = 1002). We first measured circulating DAPK-1 at 36 weeks' gestation in a nested case-control group (from Cohort 1) of 39 women who developed preeclampsia and 98 controls. We then validated our findings by measuring circulating levels in all samples from both cohorts. We also measured DAPK-1 in the circulation and placentas of women who were diagnosed with preterm preeclampsia or delivered a growth restricted infant at <34 weeks' gestation.Results: In the case-control study, circulating DAPK-1 was significantly increased in women destined to develop preeclampsia (p < 0.01). We validated this by measuring circulating levels in Cohorts 1 and 2. Again, circulating DAPK-1 was significantly higher (p < 0.001) among women destined to develop preeclampsia (Cohort 1, Area under the receiver operator characteristic curve (AUC) = 0.66; Cohort 2 AUC = 0.67). Circulating DAPK-1 was also significantly elevated in women with established preterm preeclampsia. Placental DAPK-1 mRNA and protein expression were elevated in women with established preeclampsia.Discussion: DAPK-1 is a novel placenta-enriched molecule that is elevated in the circulation of women preceding the diagnosis of preeclampsia and is likely to be secreted from the placenta. [ABSTRACT FROM AUTHOR]- Published
- 2019
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31. sFlt-1 and soluble endoglin concentrations in serum vs plasma in preterm preeclampsia: Are they interchangeable for biomarker studies?
- Author
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Brownfoot, Fiona, Kaitu'u-Lino, Tu'uhevaha, Beard, Sally, Tong, Stephen, Hannan, Natalie, and Kaitu'u-Lino, Tu'uhevaha
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PREECLAMPSIA diagnosis ,BLOOD plasma ,CELL receptors ,COMPARATIVE studies ,RESEARCH methodology ,MEDICAL cooperation ,PREECLAMPSIA ,DURATION of pregnancy ,PRENATAL diagnosis ,RESEARCH ,SERUM ,EVALUATION research ,PREDICTIVE tests ,CASE-control method ,BLOOD - Abstract
Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are increased in the circulation of women with preeclampsia. We examined whether they differ in concentration between plasma and serum samples. Maternal blood was collected and processed for serum and plasma, from 28 women with preterm preeclampsia and 18 gestation matched controls (<34weeks). Significantly higher sFlt-1 was detected in preeclamptic serum compared to plasma. Significantly higher levels of sENG were identified in serum compared to plasma from control pregnancies. Thus these data show the sample type (serum or plasma) needs to be consistent within comparisons for both sFlt-1 and sENG. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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32. Key players of the necroptosis pathway RIPK1 and SIRT2 are altered in placenta from preeclampsia and fetal growth restriction.
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Hannan, Natalie J., Beard, Sally, Binder, Natalie K., Onda, Kenji, Kaitu'u-Lino, Tu'uhevaha J., Chen, Qi, Tuohey, Laura, De Silva, Manarangi, Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha J
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PROTEIN metabolism ,BLASTOCYST ,CELL death ,FETAL growth retardation ,PLACENTA ,PREECLAMPSIA ,THIRD trimester of pregnancy ,PROTEIN kinases ,PROTEINS ,TRANSFERASES - Abstract
Introduction: Preeclampsia (PE) and fetal growth restriction (FGR) are among the leading causes of perinatal morbidity and mortality. Placental insufficiency is central to these conditions. The mechanisms underlying placental insufficiency are poorly understood. Apoptosis has long been considered the only form of regulated cell death, recent research has identified an alternate process of programmed cell death known as necroptosis [1]. Necroptosis is distinct from apoptosis, relying on the deacetylase sirtuin-2 [2], receptor interacting kinases RIPK1 and 3, and the pseudokinase MLKL [3]. We aimed to determine whether these key necroptosis effector molecules were present in human placenta and whether they are differentially expressed in severe preterm (PT) PE and FGR.Methods: PT placentas from severe early onset (<34 weeks) PE (n = 30), FGR (n = 12) and control (18) pregnancies were collected. SIRT2 and RIPK1 localization and quantitation was determined by immunohistochemistry and western blot. Immunocytochemistry was used to detect SIRT2 and RIPK1 in trophoblastic debris from first trimester, term control and PE pregnancies. Expression of SIRT2, RIPK1, RIPK3 and MLKL was examined by qPCR.Results: SIRT2 and RIPK1 were localized to the syncytiotrophoblast, villous leukocytes and vasculature in all PT placentas. A significant reduction in SIRT2 protein expression in both PE and FGR placentas was identified. RIPK1 mRNA expression was significantly increased in PE placentas. Immunofluorescence identified both SIRT2 and RIPK1 in the cytotrophoblast cytoplasm.Discussion: We have identified the presence of activators of necroptosis in human placenta. Interestingly, there is differential expression in major pregnancy complications. We conclude necroptosis may contribute to placental pathophysiology that underlies serious pregnancy complications. [ABSTRACT FROM AUTHOR]- Published
- 2017
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33. Steroid sulfatase is increased in the placentas and whole blood of women with early-onset preeclampsia.
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Gratton, Amy M., Ye, Louie, Brownfoot, Fiona C., Hannan, Natalie J., Whitehead, Clare, Cannon, Ping, Deo, Minh, Fuller, Peter J., Tong, Stephen, Kaitu'u-Lino, Tu'uhevaha J., and Kaitu'u-Lino, Tu'uhevaha J
- Abstract
Introduction: Preeclampsia is a serious complication of pregnancy affecting 5% of pregnancies. Our team identified 137 genes highly expressed in placenta relative to other human tissues. Here, we have explored a role for steroid sulfatase (STS) in preeclampsia by characterising STS expression and the functional effects of STS on primary placental trophoblasts.Methods: Characterisation of STS was performed on preterm preeclamptic and gestation-matched normotensive preterm controls who delivered at <34 weeks gestation. We characterised placental and maternal whole blood STS mRNA and placental protein expression via qRT-PCR, immunohistochemistry and Western Blot. To assess whether STS is involved in sFlt1 secretion and syncytialisation, we administered siRNA to silence STS in primary trophoblasts before measuring sFlt1 and hCG secretion and E-Cadherin expression.Results: A custom array containing 45 placental specific genes identified 10 genes significantly altered in the placentas of preeclamptic patients relative to normotensive gestation-matched controls. Of these genes, qRT-PCR and western blot on a larger cohort confirmed that the expression of STS was significantly elevated in preeclamptic placentas (n = 44) relative to gestation matched controls (n = 26). Given placental RNA leaks in to the maternal circulation, we also assessed STS mRNA expression in the whole blood of patients with preeclampsia and found it was significantly increased relative to normotensive controls. siRNA knockdown of STS in primary trophoblast resulted in a modest but significant reduction in sFlt1 secretion, but had no affect on hCG secretion or E-Cadherin protein expression.Discussion: STS is increased in preeclamptic placentas and maternal whole blood. Our data suggests that STS may affect sFlt1 secretion by regulating sFlt1-i13 transcription, and not via alterations in syncytialisation. [ABSTRACT FROM AUTHOR]- Published
- 2016
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34. Nuclear factor of activated T-cells (NFAT) regulates soluble fms-like tyrosine kinase-1 secretion (sFlt-1) from human placenta.
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Ye, Louie, Gratton, Amy, Hannan, Natalie J., Cannon, Ping, Deo, Minh, Palmer, Kirsten R., Tong, Stephen, Kaitu'u-Lino, Tu'uhevaha J., Brownfoot, Fiona C., and Kaitu'u-Lino, Tu'uhevaha J
- Abstract
Introduction: Preeclampsia is a serious complication affecting 5-8% of pregnancies. Central to its pathogenesis is placental hypoxia and inflammation which leads to secretion of soluble fms-like tyrosine kinase 1 (sFlt-1). sFlt-1 causes widespread endothelial dysfunction. The molecular mechanisms regulating sFlt-1 production remain poorly understood. Recently, a binding site for the nuclear factor activated T cells (NFAT) transcription factor has been found on fms-like tyrosine kinase 1 (FLT-1) promoter.Methods: We assessed whether inhibiting NFAT impacts FLT-1, sFlt-1 and cytokine expression, as well as sFlt-1 secretion in primary cytotrophoblasts, placental explants and human umbilical vein endothelial cells (HUVECs). We investigated whether NFAT is regulated by hypoxia in primary cytotrophoblasts. We characterised the expression of NFAT1-4 in preterm preeclamptic compared to gestationally matched placentas.Results: Inhibiting NFAT reduced FLT-1 and sFlt-1 splice variant e15a transcription, concordant with reduced total sFlt-1 and sFlt-1 e15a secretion from primary human cytotrophoblasts. This effect appeared tissue specific as inhibiting NFAT did not change sFlt-1 secretion from endothelial cells. Inhibiting NFAT also reduced transcription of inflammatory cytokines IL-1β and IL-10 in primary cytotrophoblasts. NFAT1 and NFAT3 mRNA expression were significantly increased under hypoxia (1% O2). Inhibiting NFAT under hypoxia significantly reduced FLT-1 and sFlt-1 e15a transcription, but did not reduce sFlt-1 secretion. NFAT mRNA and protein localisation was not different in preeclamptic compared to gestationally matched placenta.Discussion: NFAT positively regulates placental FLT-1 and sFlt-1 e15a, secretion of sFlt-1 and inflammatory cytokine expression. It may be involved in the pathophysiology of preeclampsia. [ABSTRACT FROM AUTHOR]- Published
- 2016
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35. Circulating adrenomedullin mRNA is decreased in women destined to develop term preeclampsia.
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Whigham, Carole-Anne, MacDonald, Teresa M., Walker, Susan P., Pritchard, Natasha, Hannan, Natalie J., Hastie, Roxanne, Alwis, Natasha De, Cannon, Ping, Nguyen, Tuong Vi, Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha
- Abstract
Preeclampsia is a pregnancy complication associated with elevated placental secretion of anti-angiogenic factors, maternal endothelial dysfunction and end-organ injury. Adrenomedullin (ADM) is a pro-angiogenic peptide hormone which regulates blood pressure and vascular integrity. It is highly expressed in both the placenta and vascular endothelial cells. We performed a nested case-control study, selected from a large prospective cohort of over 2000 participants. Circulating ADM mRNA was reduced at both 28 (n = 39 vs 248 controls, p = 0.005) and 36 weeks' of pregnancy (n = 39 vs 205 controls, p < 0.0001) in those destined to develop term preeclampsia. It was also significantly reduced in the circulation of women with established early-onset preeclampsia (n = 34 vs 21 controls, p = 0.01). ADM mRNA (n = 34 vs 12 controls) and protein (n = 53 vs 17 controls) were significantly decreased in placental tissue from women with early-onset preeclampsia (p = 0.02, p = 0.0002 respectively), suggesting the placenta is a possible source of the reduced circulating mRNA. Functional studies in primary endothelial cells revealed significantly reduced ADM mRNA expression when cells were exposed to cytotrophoblast conditioned media (derived from normotensive pregnancies, p < 0.0001) or TNFα (p < 0.0001), suggesting another possible source of reduced circulating ADM mRNA is the endothelium. Circulating ADM mRNA, but not protein, is reduced 10-12 weeks before the diagnosis of term preeclampsia. It may be of endothelial or placental origin. Whole blood mRNA is a rich source of potential biomarker discovery in the prediction of preeclampsia. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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36. EGFR (Epidermal Growth Factor Receptor) Signaling and the Mitochondria Regulate sFlt-1 (Soluble FMS-Like Tyrosine Kinase-1) Secretion.
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Hastie, Roxanne, Brownfoot, Fiona C., Pritchard, Natasha, Hannan, Natalie J., Cannon, Ping, Nguyen, Vi, Palmer, Kirsten, Beard, Sally, Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha J.
- Abstract
Preeclampsia is a hypertensive disorder of pregnancy characterized by maternal endothelial dysfunction and end-organ damage. The antiangiogenic factor, sFlt-1 (soluble FMS-like tyrosine kinase-1) has been strongly implicated in the pathogenesis of preeclampsia. sFlt-1 is secreted into the maternal circulation where it antagonizes VEGF (vascular endothelial growth factor) and ultimately disrupts vascular homeostasis. However, the upstream mechanisms regulating release of sFlt-1 are poorly characterized. We investigated the roles of key prosurvival pathways, EGFR (epidermal growth factor receptor) signaling, and the mitochondria, in regulating sFlt-1 production. We initially found that the mRNA and protein of EGFR and downstream adaptor molecules were significantly increased in preeclamptic placental tissue relative to normotensive controls. Inhibiting the EGFR signaling cascade using siRNA (small interfering ribonucleic acid) or small molecule inhibitors significantly reduced sFlt-1 release from primary cytotrophoblast (placental cells). Additionally, inhibiting the mitochondrial electron transport chain or activating downstream energy-sensing molecules (AMPK [AMP-activated kinase], SIRT1 [sirtuin 1 ], and PGC1α [PPAR-γ co-activator 1]) also significantly reduced sFlt-1 secretion from cytotrophoblast cells, without affecting EGFR signaling. In vivo, treating pregnant mice with gefitinib (an EGFR inhibitor) or resveratrol (perturbs mitochondrial function) significantly reduced circulating murine sFlt-1 compared with vehicle control. Furthermore, treating primary cytotrophoblasts with therapeutics which have been previously found to reduce sFlt-1 secretion, either reduced EGFR signaling (esomeprazole and statins) or perturbed mitochondrial function (esomeprazole, resveratrol, and metformin). Additionally, targeting both pathways simultaneously produced additive reductions in sFlt-1 secretion. Thus, we have identified 2 key survival pathways that seem to be overactive in preeclampsia and involved in the regulation of placental sFlt-1 secretion. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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37. Disulfiram inhibits placental soluble FMS-like tyrosine kinase-1 and soluble endoglin secretion independent of the proteasome.
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Hastie, Roxanne, Ye, Louie, Hannan, Natalie J., Brownfoot, Fiona C., Cannon, Ping, Nguyen, Vi, Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha J.
- Subjects
RNA metabolism ,CELL receptors ,DISULFIRAM ,ENZYME inhibitors ,ENZYME-linked immunosorbent assay ,EPITHELIAL cells ,PLACENTA ,PREECLAMPSIA ,PROTEOLYTIC enzymes ,PHARMACODYNAMICS - Abstract
Preeclampsia is associated with intermittent placental hypoxia, inflammation and the release of antiangiogenic factors, namely sFLT-1 and sEng. These factors cause maternal endothelial dysfunction and the manifestation of clinical disease. Disulfiram is a dehydrogenase inhibitor used to treat alcoholism and has been suggested as a proteasome inhibitor. Inhibiting the proteasome has been previously shown to reduce FLT-1 gene expression. Thus, we aim to investigate whether disulfiram alters the secretion of sFLT-1 and sEng and reduces endothelial dysfunction. METHODS AND RESULTS: We assessed the effects of disulfiram on primary cytotrophoblast and human umbilical vein endothelial cells (HUVECs). Disulfiram significantly reduced mRNA expression of membrane bound FLT-1 and sFLT-1 variants in primary cytotrophoblasts, which translated into a significant reduction in the protein secretion of sFLT-1. Additionally, sFLT-1 was reduced in primary HUVECs treated with disulfiram, whilst sEng was only reduced in primary cytotrophoblasts. Next, we investigated the effect of disulfiram on endothelial dysfunction using primary HUVECs treated with 5% preeclamptic serum ± disulfiram. Serum from preeclamptic women induced endothelial dysfunction evidenced by increased mRNA expression of vascular cell adhesion molecule-1 (VCAM-1) and adhesion of peripheral blood mononuclear cells (PBMCs) to HUVECs. The addition of disulfiram reduced VCAM-1 mRNA expression, however did not affect the adhesion of PBMCs to endothelial cells. Lastly, we assessed the effects of disulfiram on the 20S subunit of the proteasome and found disulfiram did not inhibit this subunit in either primary cytotrophoblast or HUVECs. CONCLUSIONS: Disulfiram quenches sFLT-1 and sEng via mechanisms independent of the 20S subunit of the proteasome. Understanding of the mechanisms by which disulfiram inhibits antiangiogenic secretion may reveal insights into the pathogenesis and potential therapeutic targets for preeclampsia. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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38. EGFL7 gene expression is regulated by hypoxia in trophoblast and altered in the plasma of patients with early preeclampsia.
- Author
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Whitehead, Clare L., Kaitu'u-Lino, Tu'uhevaha J., Binder, Natalie K., Beard, Sally, De Alwis, Natasha, Brownfoot, Fiona, Tong, Stephen, and Hannan, Natalie J.
- Subjects
BLASTOCYST ,GENE expression ,PLACENTA ,PREECLAMPSIA ,CASE-control method ,ENDOTHELIAL growth factors - Abstract
Introduction: Preeclampsia is a severe complication of pregnancy, and likely arises from abnormal placental development in early pregnancy. Persistent placental hypoxia is thought to trigger the release of anti-angiogenic factors into the maternal circulation leading to widespread endothelial dysfunction. Epidermal growth factor-like domain 7 (EGFL7) is a secreted angiogenic factor that may play a key role in the disrupted angiogenesis seen in response to placental hypoxia that characterizes preeclampsia.Methods: Primary trophoblasts were isolated and cultured in both normoxic and hypoxic conditions. Under hypoxia HIF1α was silenced and EGFL7 mRNA expression was assessed. EGFL7 mRNA expression was measured in placentas obtained from women with early (<34 weeks) and late onset preeclampsia; and in peripheral whole blood maternal samples from women with preeclampsia and gestation matched controls. EGFL7 plasma levels were assessed in plasma from women with preeclampsia, compared to gestation-matched controls.Results: EGFL7 expression was significantly upregulated in primary human trophoblasts cultured in hypoxia (>2-fold, p < 0.0001), however this was not regulated via a HIF1α dependent manner. EGFL7 mRNA expression was not altered in placenta from women with early or late onset preeclampsia. Circulating EGFL7 protein levels were not different in women with severe preeclampsia. In contrast, EGFL7 mRNA expression was increased in maternal blood in women with early onset preeclampsia (∼1.6-fold, p < 0.05).Discussion: EGFL7 mRNA expression is increased with hypoxia in human trophoblast and is increased in the maternal circulation in women with preeclampsia. Further studies aimed at understanding the role and regulation of EGLF7 in the pathophysiology of preeclampsia are required. [ABSTRACT FROM AUTHOR]- Published
- 2018
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39. Loss of Akt increases soluble endoglin release from endothelial cells but not placenta.
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Kaitu’u-Lino, Tu’uhevaha J., Hastie, Roxanne, Hannan, Natalie J., Brownfoot, Fiona, De Silva, Manarangi, Cannon, Ping, Tuohey, Laura, Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha J
- Subjects
PROTEIN metabolism ,BIOCHEMISTRY ,CELLULAR signal transduction ,EPITHELIAL cells ,PHENOMENOLOGY ,PHOSPHOTRANSFERASES ,PLACENTA ,POLYMERASE chain reaction ,PREECLAMPSIA ,PROTEOLYTIC enzymes ,TRANSFERASES ,WESTERN immunoblotting ,CASE-control method ,REVERSE transcriptase polymerase chain reaction ,CHEMICAL inhibitors - Abstract
Introduction: Preeclampsia is a serious pregnancy complication for which there are no medical treatments. Soluble endoglin is an anti-angiogenic factor implicated in the pathogenesis of the disease, however little is known about its molecular regulation. The PI3K/Akt pathway is down regulated in preeclamptic placentas and decreased PI3K/Akt signaling has been linked to increased soluble endoglin release from endothelial cells. MMP14 is a key protease that functions to release soluble endoglin from the placental surface.Objective: This study aimed to determine whether reduced placental PI3K/Akt causes elevated release of soluble endoglin via MMP14.Study Design: Akt mRNA and protein expression were assessed in early onset preeclamptic and preterm control placentas (delivered <34weeks gestation). PI3K/Akt inhibition was achieved by administering PI3K inhibitor wortmannin, a specific Akt inhibitor or Akt siRNA to primary human umbilical vein endothelial cells, primary trophoblast and placental explants. The effect of PI3K/Akt inhibition on soluble endoglin release, MMP14, endoglin and TIMP-3 mRNA expression was determined.Results: We identified significantly reduced pAkt and total Akt in preeclamptic placentas relative to preterm control. Inhibition of PI3K/Akt resulted in significantly elevated soluble endoglin release from HUVECs, had no effect on MMP14 mRNA expression but resulted in significantly reduced TIMP3. In contrast inhibiting PI3K/Akt in placental explants or primary trophoblast did not change soluble endoglin release.Conclusion: This study confirms that the PI3K/Akt cell protection pathway is down regulated in preeclampsia, but demonstrates that this dysregulation is unlikely to be responsible for the excessive placental soluble endoglin release characteristic of preeclampsia. [ABSTRACT FROM AUTHOR]- Published
- 2016
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40. A wash step at collection of placental biopsies from preeclamptic pregnancies does not adversely affect levels of sFlt-1 or endoglin.
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Kaitu’u-Lino, Tu’uhevaha J., Hannan, Natalie J., De Silva, Manarangi, Binder, Natalie, Tuohey, Laura, Cannon, Ping, Tong, Stephen, and Kaitu'u-Lino, Tu'uhevaha J
- Subjects
PREECLAMPSIA diagnosis ,ANTIGENS ,BIOPSY ,CELL receptors ,PLACENTA ,PREECLAMPSIA ,BODY mass index ,PREDICTIVE tests ,CASE-control method - Abstract
There is recent interest for uniform placental collection protocols so laboratories can share samples. However, concerns have been raised a wash step at collection causes significant loss of sFlt-1 and soluble endoglin, among the most studied proteins in placentology. We measured Flt-1 and endoglin mRNA and protein in 10 preeclamptic placentas that were washed, or left unwashed. Reassuringly, there was no significant change in the Flt-1, sFlt-1-e15a or sFlt-1-i13 mRNA or Flt-1 or sFlt-1 protein expression or localization. There was also no change in endoglin mRNA expression or protein localization. Washing preeclamptic placental samples does not alter anti-angiogenic factor expression. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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41. Effect of sildenafil citrate on circulating levels of sFlt-1 in preeclampsia.
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Brownfoot, Fiona C., Tong, Stephen, Hannan, Natalie J., Cannon, Ping, Nguyen, Vi, and Kaitu'u-Lino, Tu'uhevaha J.
- Abstract
Objectives: To examine the effect of sildenafil on level of antiangiogenic proteins of preeclampsia. Firstly to examine the effect of sildenafil on serum biomarkers in a patient with preterm preeclampsia. Secondly, to examine the effect of sildenafil on sFlt-1 and soluble endoglin secretion from primary trophoblasts and placental explants.Study Design: The clinical team administered 50 mg tds sildenafil to a 26-year-old primigravid woman with severe preeclampsia at the threshold of viability (24 3/7 weeks gestation) and we collected bloods to examine the effect of slidenafil on antiangiogenic factors sFlt-1 and soluble endoglin (sENG), pro-angiogenic factor PlGF and vascular cell adhesion molecule 1 (VCAM-1) and endothelin-1 (ET1). We administered sildenafil to human primary trophoblasts and placental explants and explored its effect on sFlt-1 and sENG secretion.Main Outcome Measures: We examined serum anti-angiogenic factors sFlt-1 and sENG, pro-angiogenic factor PlGF, the potent vasoconstrictor ET1 and VCAM-1 by ELISA. We explored the effect of sildenafil on sFlt-1 secretion from primary trophoblasts and sFlt-1 and sENG secretion from placental explants.Results: We found a reduction in serum sFlt-1, stabilisation in sENG and PlGF in a patient with peri-viable preterm preeclampsia administered oral sildenafil 50 mg three times daily (tds). Furthermore there was an initial stabilisation in serum VCAM-1 and a decline in ET1 with sildenafil administration. This was concordant with stabilisation of clinical and biochemical features of preeclampsia. Interestingly, treating placental cells and tissues in vitro with sildenafil did not appear to change sFlt-1 or sENG secretion.Conclusion: Sildenafil administration was associated with a reduction in serum sFlt-1 and sENG secretion and increase in PlGF secretion in a patient with preterm preeclampsia, potentially via increasing placental perfusion rather than acting directly on the placenta. [ABSTRACT FROM AUTHOR]- Published
- 2018
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42. Melatonin enhances antioxidant molecules in the placenta, reduces secretion of soluble fms-like tyrosine kinase 1 (sFLT) from primary trophoblast but does not rescue endothelial dysfunction: An evaluation of its potential to treat preeclampsia.
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Hannan, Natalie J., Binder, Natalie K., Beard, Sally, Nguyen, Tuong-Vi, Kaitu’u-Lino, Tu’uhevaha J., and Tong, Stephen
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PHYSIOLOGICAL effects of melatonin ,ANTIOXIDANTS ,PLACENTA physiology ,TROPHOBLAST ,PROTEIN-tyrosine kinases ,ENDOTHELIAL cells ,PREECLAMPSIA ,THERAPEUTICS - Abstract
Preeclampsia is one of the most serious complications of pregnancy. Currently there are no medical treatments. Given placental oxidative stress may be an early trigger in the pathogenesis of preeclampsia, therapies that enhance antioxidant pathways have been proposed as treatments. Melatonin is a direct free-radical scavenger and indirect antioxidant. We performed in vitro assays to assess whether melatonin 1) enhances the antioxidant response element genes (heme-oxygenase 1, (HO-1), glutamate-cysteine ligase (GCLC), NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), thioredoxin (TXN)) or 2) alters secretion of the anti-angiogenic factors soluble fms-like tyrosine kinase-1 (sFLT) or soluble endoglin (sENG) from human primary trophoblasts, placental explants and human umbilical vein endothelial cells (HUVECs) and 3) can rescue TNF-α induced endothelial dysfunction. In primary trophoblast melatonin treatment increased expression of the antioxidant enzyme TXN. Expression of TXN, GCLC and NQO1 was upregulated in placental tissue with melatonin treatment. HUVECs treated with melatonin showed an increase in both TXN and GCLC. Melatonin did not increase HO-1 expression in any of the tissues examined. Melatonin reduced sFLT secretion from primary trophoblasts, but had no effect on sFLT or sENG secretion from placental explants or HUVECs. Melatonin did not rescue TNF-α induced VCAM-1 and ET-1 expression in endothelial cells. Our findings suggest that melatonin induces antioxidant pathways in placenta and endothelial cells. Furthermore, it may have effects in reducing sFLT secretion from trophoblast, but does not reduce endothelial dysfunction. Given it is likely to be safe in pregnancy, it may have potential as a therapeutic agent to treat or prevent preeclampsia. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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43. Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction – implications for treating preeclampsia.
- Author
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Kaitu’u-Lino, Tu’uhevaha J., Brownfoot, Fiona C., Beard, Sally, Cannon, Ping, Hastie, Roxanne, Nguyen, Tuong V., Binder, Natalie K., Tong, Stephen, and Hannan, Natalie J.
- Subjects
- *
METFORMIN , *ESOMEPRAZOLE , *COMBINATION drug therapy , *ENDOTHELIUM diseases , *PREECLAMPSIA , *THERAPEUTICS - Abstract
Introduction: The discovery of new treatments that prevent or treat preeclampsia would be a major advance. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. We recently identified metformin and esomeprazole as potential treatments for preeclampsia. Both reduce placental and endothelial secretion of sFlt-1 and soluble endoglin, and reduce endothelial dysfunction. Objectives: We set out to assess whether combining metformin and esomeprazole would additively reduce sFlt-1 and soluble endoglin secretion and reduce endothelial dysfunction (verses drug alone). Metformin and esomeprazole were added to primary placental cells and tissues, and endothelial cells and their effects on sFlt-1 and soluble endoglin secretion were assessed in vitro. Tumor necrosis factor-α (TNF-α) was added to endothelial cells to induce dysfunction in vitro. We examined the ability of metformin + esomeprazole to rescue TNF-α induced vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (ET-1) expression, leukocyte adhesion (markers of endothelial dysfunction). Results: Combining metformin and esomeprazole was additive at reducing sFlt-1 secretion and expression of sFlt-1 e15a mRNA isoform in primary cytotrophoblast, placental explants and endothelial cells. In contrast, no additive reduction in sENG was observed with combined metformin and esomeprazole. The low-dose combination of metformin + esomeprazole additively reduced TNF-α-induced VCAM-1 mRNA, but not VCAM-1 protein expression. There was no additive reduction when combining metformin and esomeprazole on TNF-α induced PBMC adhesion to endothelial cells. However, combining metformin and esomeprazole additively reduced ET-1 mRNA expression. Conclusions: In conclusion combining metformin and esomeprazole additively reduced secretion of sFlt-1, and markers of endothelial dysfunction. The combination of metformin and esomeprazole may provide a more effective treatment or prevention for preeclampsia compared to either as single agents. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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44. Activating Transcription Factor 3 Is Reduced in Preeclamptic Placentas and Negatively Regulates sFlt-1 (Soluble fms-Like Tyrosine Kinase 1), Soluble Endoglin, and Proinflammatory Cytokines in Placenta.
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Kaitu'u-Lino, Tu'uhevaha J., Brownfoot, Fiona C., Hastie, Roxanne, Chand, Ashwini, Cannon, Ping, Deo, Minh, Tuohey, Laura, Whitehead, Clare, Hannan, Natalie J., and Tong, Stephen
- Abstract
Preeclampsia is a major pregnancy complication associated with poor placental perfusion and placental hypoxia. Systemic and placental inflammation and elevated placental secretion of the antiangiogenic factors sFlt-1 (soluble fms-like tyrosine kinase 1) and sEng (soluble endoglin) are hallmarks of preeclampsia, causing endothelial dysfunction and multiorgan injury. A molecule that links placental hypoxia, inflammation, and antiangiogenic factor release has not been described. ATF3 (activating transcription factor 3) is highly expressed in placenta. We assessed whether placental ATF3 is dysregulated in preterm preeclampsia, is altered by hypoxia, and regulates proinflammatory cytokine and antiangiogenic factor production. ATF3 mRNA and protein expression was significantly reduced in preterm preeclamptic placentas compared with gestation-matched controls. Hypoxia reduced ATF3 expression in primary cytotrophoblast and placental explants. Silencing ATF3 in primary cytotrophoblast increased proinflammatory cytokine (IL-6 [interleukin 6], TNF-α [tumor necrosis factor α]) and NF-κB (nuclear factor κB) expression. In silico analysis identified an ATF3-binding site in the promoter of Flt-1 (the transcript from which sFlt-1 is produced). Silencing ATF3 increased sFlt-1 and sEng secretion from primary cytotrophoblast possibly by increasing Rab11a and Arf1, cargo proteins that facilitate exosomal release of sFlt-1. ATF3 knockout mice did not have a preeclampsia phenotype, suggesting that these pathways may be specific to humans (preeclampsia is a uniquely human condition). To conclude, we have shown that ATF3 is decreased in preeclamptic placentas and that this decrease is likely to occur after prolonged hypoxia. We show that ATF3 is a regulator of placental proinflammatory cytokines and antiangiogenic factors sFlt-1 and sEng. Therefore, reduced ATF3 may be centrally involved in the pathology of preeclampsia. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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45. Maternal plasma concentrations of the placental specific sFLT-1 variant, sFLT-1 e15a, in fetal growth restriction and preeclampsia.
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Palmer, Kirsten R., Kaitu'u-Lino, Tu'uhevaha J., Cannon, Ping, Tuohey, Laura, De Silva, Manarangi S., Varas-Godoy, Manuel, Acuña, Stephanie, Galaz, José, Tong, Stephen, and Illanes, Sebastián E.
- Subjects
- *
FETAL development , *GESTATIONAL age , *VASCULAR endothelial growth factors , *PREECLAMPSIA prevention , *PREGNANCY , *CELL receptors , *ENZYME-linked immunosorbent assay , *FETAL growth retardation , *LONGITUDINAL method , *NONPARAMETRIC statistics , *PLACENTA , *PREECLAMPSIA , *CASE-control method , *BLOOD - Abstract
Objective: sFLT-1 e15a is a recently described sFlt-1 variant that is placental and primate specific. As such, it may have potential as a biomarker. Using a newly developed ELISA, we measured maternal plasma sFLT-1 e15a levels in women with fetal growth restriction and pre-eclampsia.Method: We performed a nested case-control study where we measured total sFLT-1 and sFLT-1 e15a plasma protein concentrations. Samples, selected from a prospective cohort study, consisted of 87 healthy controls, 11 cases that developed term preeclampsia and 20 cases where there was fetal growth restriction. We also measured sFLT-1 and sFLT-1 e15a plasma concentrations in a separate cohort: 15 cases of preterm preeclampsia and 24 healthy controls.Results: The prospective case-control cohort demonstrated significantly increased sFLT-1 e15a among cases with term fetal growth restriction (p < 0.05). We also observed that total sFLT-1 (this ELISA indiscriminately detects all variants) was significantly increased in term preeclampsia (p < 0.0001), but not fetal growth restriction. The separate cohort of early-onset preeclamptics showed significantly increased sFLT-1 e15a levels (p < 0.0001).Conclusion: Plasma sFLT-1 e15a is significantly increased in early-onset preeclampsia and term fetal growth restriction. Further assessment of the benefit for sFLT-1 e15a testing in prediction or diagnosis of these disease states is warranted. [ABSTRACT FROM AUTHOR]- Published
- 2017
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46. Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction.
- Author
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Kenji Onda, Tong, Stephen, Beard, Sally, Binder, Natalie, Masanaga Muto, Senadheera, Sevvandi N., Parry, Laura, Dilworth, Mark, Renshall, Lewis, Brownfoot, Fiona, Hastie, Roxanne, Tuohey, Laura, Palmer, Kirsten, Toshihiko Hirano, Masahito Ikawa, Kaitu'u-Lino, Tu'uhevaha, Hannan, Natalie J., Onda, Kenji, Muto, Masanaga, and Hirano, Toshihiko
- Abstract
Preeclampsia is a severe complication of pregnancy. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. Oxidative stress and vascular inflammation exacerbate the endothelial injury. A drug that can block these pathophysiological steps would be an attractive treatment option. Proton pump inhibitors (PPIs) are safe in pregnancy where they are prescribed for gastric reflux. We performed functional studies on primary human tissues and animal models to examine the effects of PPIs on sFlt-1 and soluble endoglin secretion, vessel dilatation, blood pressure, and endothelial dysfunction. PPIs decreased sFlt-1 and soluble endoglin secretion from trophoblast, placental explants from preeclamptic pregnancies, and endothelial cells. They also mitigated tumor necrosis factor-α-induced endothelial dysfunction: PPIs blocked endothelial vascular cell adhesion molecule-1 expression, leukocyte adhesion to endothelium, and disruption of endothelial tube formation. PPIs decreased endothelin-1 secretion and enhanced endothelial cell migration. Interestingly, the PPI esomeprazole vasodilated maternal blood vessels from normal pregnancies and cases of preterm preeclampsia, but its vasodilatory effects were lost when the vessels were denuded of their endothelium. Esomeprazole decreased blood pressure in a transgenic mouse model where human sFlt-1 was overexpressed in placenta. PPIs upregulated endogenous antioxidant defenses and decreased cytokine secretion from placental tissue and endothelial cells. We have found that PPIs decrease sFlt-1 and soluble endoglin secretion and endothelial dysfunction, dilate blood vessels, decrease blood pressure, and have antioxidant and anti-inflammatory properties. They have therapeutic potential for preeclampsia and other diseases where endothelial dysfunction is involved. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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47. Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta.
- Author
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Brownfoot, Fiona C., Tong, Stephen, Hannan, Natalie J., Hastie, Roxanne, Cannon, Ping, and Kaitu'u-Lino, Tu'uhevaha J.
- Subjects
PREECLAMPSIA ,PROTEIN-tyrosine kinases ,ENDOGLIN ,STATINS (Cardiovascular agents) ,TROPHOBLAST ,PREGNANCY ,ANTILIPEMIC agents ,BIOCHEMISTRY ,BLASTOCYST ,CELL receptors ,EPITHELIAL cells ,PHENOMENOLOGY ,OXIDOREDUCTASES ,PLACENTA ,PREGNANCY proteins ,PRAVASTATIN ,SIMVASTATIN ,PHARMACODYNAMICS - Abstract
Background: Preeclampsia is associated with the placental release of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG). These anti-angiogenic factors cause hypertension and multi-organ injury. Pravastatin decreases placental secretion of sFlt-1 in vitro and is currently being examined in clinical trials as a potential treatment for preeclampsia. However, it is possible that different classes of statins may be more potent at decreasing sFlt-1 secretion. We compared the relative potency of three different generations of statins on sFlt-1 and sENG secretion from human endothelial cells, trophoblast cells, and placenta explants.Methods: We performed functional experiments using primary human umbilical vein endothelial cells, trophoblast cells and preterm preeclamptic placental explants to assess the affect of simvastatin, rosuvastatin and pravastatin on sFlt-1 and sENG secretion and compared the relative potency of each statin at reducing these factors (Inhibitory Concentration 50). Furthermore we assessed the effect of each statin on the antioxidant and cytoprotective enzyme, heme-oxygenase 1.Results: All statins reduced sFlt-1 secretion from endothelial cells, trophoblasts and preterm preeclamptic placental explants. Simvastatin was the most potent inhibitor of sFlt-1 secretion from endothelial cells (IC 50 3.2 μM), trophoblast cells (IC 50 61.4 μM) and placental explants. Simvastatin was 28 times and 3 times more potent at reducing sFlt-1 secretion from endothelial cells and 85 times and 33 times more potent at reducing sFlt-1 secretion from trophoblast cells than pravastatin or rosuvastatin respectively. All statins increased sENG secretion from endothelial cells however did not change secretion from placental explants. While all statins up-regulated heme-oxygenase 1 in endothelial cells, only simvastatin up-regulated its expression in placenta from patients with preterm preeclampsia.Conclusion: Simvastatin may be a more potent inhibitor of sFlt-1 secretion from endothelial cells, trophoblast cells and placenta from women with preterm preeclampsia than either pravastatin or rosuvastatin. [ABSTRACT FROM AUTHOR]- Published
- 2016
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48. Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity.
- Author
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Palmer, Kirsten R., Kaitu'u-Lino, Tu'uhevaha J., Hastie, Roxanne, Hannan, Natalie J., Ye, Louie, Binder, Natalie, Cannon, Ping, Tuohey, Laura, Johns, Terrance G., Shub, Alexis, and Tong, Stephen
- Abstract
In preeclampsia, the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFLT-1) is released from placenta into the maternal circulation, causing endothelial dysfunction and organ injury. A recently described splice variant, sFLT-1 e15a, is primate specific and the most abundant placentally derived sFLT-1. Therefore, it may be the major sFLT-1 isoform contributing to the pathophysiology of preeclampsia. sFLT-1 e15a protein remains poorly characterized: its bioactivity has not been comprehensively examined, and serum levels in normal and preeclamptic pregnancy have not been reported. We generated and validated an sFLT-1 e15a-specific ELISA to further characterize serum levels during pregnancy, and in the presence of preeclampsia. Furthermore, we performed assays to examine the bioactivity and antiangiogenic properties of sFLT-1 e15a protein. sFLT-1 e15a was expressed in the syncytiotrophoblast, and serum levels rose across pregnancy. Strikingly, serum levels were increased 10-fold in preterm preeclampsia compared with normotensive controls. We confirmed sFLT-1 e15a is bioactive and is able to inhibit vascular endothelial growth factor signaling of vascular endothelial growth factor receptor 2 and block downstream Akt phosphorylation. Furthermore, sFLT-1 e15a has antiangiogenic properties. sFLT-1 e15a decreased endothelial cell migration, invasion, and inhibited endothelial cell tube formation. Administering sFLT-1 e15a blocked vascular endothelial growth factor induced sprouts from mouse aortic rings ex vivo. We have demonstrated that sFLT-1 e15a is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Future development of diagnostics and therapeutics for preeclampsia should consider targeting placentally derived sFLT-1 e15a. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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49. Heme Oxygenase-1 Is Not Decreased in Preeclamptic Placenta and Does Not Negatively Regulate Placental Soluble fms-Like Tyrosine Kinase-1 or Soluble Endoglin Secretion.
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Tong, Stephen, Kaitu'u-Lino, Tu'uhevaha J., Onda, Kenji, Beard, Sally, Hastie, Roxanne, Binder, Natalie K., Cluver, Cathy, Tuohey, Laura, Whitehead, Clare, Brownfoot, Fiona, De Silva, Manarangi, and Hannan, Natalie J.
- Abstract
Elevated placental release of the antiangiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG), is central to the pathophysiology of preeclampsia. It is widely accepted that heme oxygenase-1 (HO-1) is decreased in preeclamptic placenta and negatively regulates sFlt-1 and sENG production. We set out to verify these contentions. There was no difference in HO-1 mRNA or protein levels in preterm preeclamptic placentas (n=17) compared with gestationally matched controls (n=27). In silico analysis of microarray studies did not identify decreased placental HO-1 expression in preeclamptic placenta. Silencing HO-1 in primary trophoblasts did not affect sFlt-1 protein secretion after 24 or 48 hours. Silencing nuclear factor (erythroid-derived 2)-like 2 (transcription factor that upregulates HO-1) in trophoblasts also did not affect sFlt-1 secretion. Administering tin protoporphyrin IX dichloride (HO-1 inhibitor) or cobalt protoporphyrin (HO-1 inducer) into placental explants did not affect sFlt-1 or sENG secretion. Silencing HO-1 in 2 types of primary endothelial cells (human umbilical vein endothelial and uterine microvascular endothelial cells) significantly increased sFlt-1 secretion but not sENG secretion. However, HO-1 silencing selectively increased mRNA expression of sFlt-1 i13 (generically expressed sFlt-1 variant) but not of sFlt-1 e15a (sFlt-1 variant mainly expressed in placenta). Furthermore, adding tin protoporphyrin IX dichloride decreased sFlt-1, whereas adding HO-1 inducers (cobalt protoporphyrin, dimethyl fumarate, and rosiglitazone) either had no effect or increased sFlt-1 or sENG secretion (these trends are opposite to what is expected). We conclude that HO-1 expression is not decreased in preeclamptic placenta and HO-1 does not negatively regulate placental sFlt-1 and sENG secretion in placental or endothelial cells. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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50. Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia.
- Author
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Brownfoot, Fiona C., Tong, Stephen, Hannan, Natalie J., Binder, Natalie K., Walker, Susan P., Cannon, Ping, Hastie, Roxanne, Kenji Onda, and Kaitu'u-Lino, Tu'uhevaha J.
- Abstract
Preeclampsia is a major pregnancy complication where excess placental release of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin causes maternal endothelial and multisystem organ injury. Clinical trials have commenced examining whether pravastatin can be used to treat preeclampsia. However, the preclinical evidence supporting pravastatin as a treatment is limited to animal models, with almost no studies in human tissues. Therefore, we examined whether pravastatin reduced sFlt-1 and soluble endoglin secretion and decreased endothelial dysfunction in primary human tissues. Pravastatin reduced sFlt-1 secretion from primary endothelial cells, purified cytotrophoblast cells, and placental explants obtained from women with preterm preeclampsia. It increased soluble endoglin secretion from endothelial cells but did not change secretion from placental explants. The regulation of sFlt-1 by pravastatin seemed to be mediated via the 3-hydroxy-3-methylglutaryl-coenzyme A reductase cholesterol synthesis pathway. Pravastatin also reduced markers of endothelial dysfunction, including vascular cell adhesion molecule-1 expression and leukocyte adhesion on endothelial cells and increased endothelial cell migration and invasion. We also treated 4 patients with preterm preeclampsia presenting at <30 weeks of gestation with daily pravastatin. Pravastatin seemed to stabilize blood pressure, proteinuria, and serum uric acid levels. Furthermore, serum sFlt-1 levels decreased. We collected the placentas at delivery and found that pravastatin reduced sFlt-1 secretion. These results indicate that pravastatin reduced sFlt-1 and soluble endoglin production and decreased endothelial dysfunction in primary human tissues. We also present pilot data, suggesting that pravastatin can stabilize clinical and biochemical features of preterm preeclampsia. Our data obtained in human tissues support the concept that pravastatin is a candidate therapeutic for preeclampsia. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
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