Personalized Therapy Against Preeclampsia by Replenishing Placental Protein 13 (PP13) Targeted to Patients With Impaired PP13 Molecule or Function

2011 Nyarko, 2016, Prevalence and sociodemographic determinants of hypertension history among women in reproductive age in Ghana, Int J Hypertens, 2016, 10.1155/2016/3292938 Schellack, 2015, Hypertension: a review of antihypertensive medication, past and present, S Afr Pharm J, 82, 17 World health statistics Go, 2014, An effective approach to high blood pressure control — a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention, Hypertension, 63, 878, 10.1161/HYP.0000000000000003 Bacon, 2004, Effects of exercise, diet and weight loss on high blood pressure, Sports Med, 34, 307, 10.2165/00007256-200434050-00003 Puzserova, 2016, Blood pressure regulation in stress: focus on nitric oxide-dependent mechanisms, Physiol Res, 65, S309, 10.33549/physiolres.933442 Della Corte, 2016, Inflammation, endothelial dysfunction and arterial stiffness as therapeutic targets in cardiovascular medicine, Curr Pharm Des, 22, 4658, 10.2174/1381612822666160510124801 Cuffee, 2014, Psychosocial risk factors for hypertension: an update of the literature, Curr Hypertens Rep, 16, 1 Eisenberg, 2016, Diabetes, medical comorbidities and couple fecundity, Hum Reprod, 31, 2369, 10.1093/humrep/dew200 Imaizumi, 2016, A Cushing's syndrome patient's severe insomnia and morning blood pressure surge both improved after her left adrenal tumor resection, Blood Press Monit, 21, 361, 10.1097/MBP.0000000000000206 Graham, 2016, Racial and ethnic differences in acute coronary syndrome and myocardial infarction within the United States: from demographics to outcomes, Clin Cardiol, 39, 299, 10.1002/clc.22524 Walker, 2000, Pre-eclampsia, Lancet, 356, 1260, 10.1016/S0140-6736(00)02800-2 Roberts, 2001, Pathogenesis and genetics of pre-eclampsia, Lancet, 357, 53, 10.1016/S0140-6736(00)03577-7 Redman, 2005, Latest advances in understanding preeclampsia, Science, 308, 1592, 10.1126/science.1111726 Moodley, 2015, 1 Sibai, 2012, Hypertension, 631 March of Dimes Fisk, 2009, Systematic analysis of research funding in maternal and perinatal health, Br J Obstet Gynaecol, 116, 347, 10.1111/j.1471-0528.2008.02027.x Witcher, 2015, Maternal morbidity and mortality: identifying opportunities to improve clinical outcomes, J Perinat Neonatal Nurs, 29, 202, 10.1097/JPN.0000000000000112 American Biopharmaceutical, 2013, The drug discovery, development and approval process, 1 Garcia Benavidas, 2016, New pharmacological opportunities for prevention of preeclampsia, J Clin Exp Cardiol, 7, 1 Duley, 2009, The global impact of pre-eclampsia and eclampsia, Semin Perinatol, 33, 130, 10.1053/j.semperi.2009.02.010 Riding, 2013, The thalidomide disaster, lessons from the past, Methods Mol Biol, 947, 575, 10.1007/978-1-62703-131-8_36 Goodman, 2011, The long-term effects of in utero exposures—the DES story, N Engl J Med, 364, 2083, 10.1056/NEJMp1104409 Podymow, 2008, Update on the use of antihypertensive drugs in pregnancy, Hypertension, 51, 960, 10.1161/HYPERTENSIONAHA.106.075895 Sibai, 1987, A comparison of labetalol plus hospitalization versus hospitalization alone in the management of preeclampsia remote from term, Obstet Gynecol, 70, 323 Shmueli, 2012, Economic assessment of screening for pre-eclampsia, Prenat Diagn, 32, 29, 10.1002/pd.2871 von Ehr, 2016, Implications of maternal conditions and pregnancy course on offspring's medical problems in adult life, Arch Gynecol Obstet, 294, 673, 10.1007/s00404-016-4178-7 Godfrey, 2001, Fetal programming and adult health, Public Health Nutr, 4, 611, 10.1079/PHN2001145 Irgens, 2011, Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study, Br Med J, 323, 1213, 10.1136/bmj.323.7323.1213 McDonald, 2008, Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses, Am Heart J, 156, 918, 10.1016/j.ahj.2008.06.042 Seely, 2015, Preeclampsia and future cardiovascular disease in women: how good are the data and how can we manage our patients?, Semin Perinatol, 39, 276, 10.1053/j.semperi.2015.05.006 Lee, 2015, Preeclampsia and the risk of cardiovascular disease later in life — a review of the evidence, Midwifery, 31, 1127, 10.1016/j.midw.2015.09.005 England, 2015, Preeclampsia in pregnancy and later use of antihypertensive drugs, Eur J Epidemiol, 30, 501, 10.1007/s10654-015-0018-5 Macdonald-Wallis, 2012, Blood pressure change in normotensive, gestational hypertensive, preeclamptic, and essential hypertensive pregnancies, Hypertension, 59, 1241, 10.1161/HYPERTENSIONAHA.111.187039 Bokslag, 2016, Preeclampsia; short and long-term consequences for mother and neonate, Early Hum Dev, 102, 47, 10.1016/j.earlhumdev.2016.09.007 Fraser, 2013, Cohort profile: the Avon longitudinal study of parents and children: ALSPAC mothers cohort, Int J Epidemiol, 42, 97, 10.1093/ije/dys066 Roberts, 2011, The role of obesity in preeclampsia, Pregnancy Hypertens, 1, 6, 10.1016/j.preghy.2010.10.013 Persson, 2016, Maternal overweight and obesity and risk of pre-eclampsia in women with type 1 diabetes or type 2 diabetes, Diabetologia, 59, 2099, 10.1007/s00125-016-4035-z 2016, Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants, Lancet, 387, 1377, 10.1016/S0140-6736(16)30054-X Bushnell, 2014, Guidelines for the prevention of stroke in women, Stroke, 45, 1545, 10.1161/01.str.0000442009.06663.48 Osol, 2014, Preeclampsia and maternal cardiovascular disease: consequence or predisposition?, J Vasc Res, 51, 290, 10.1159/000367627 Hahn, 2015, Preeclampsia – will orphan drug status facilitate innovative biological therapies?, Front Surg, 2, 7.1, 10.3389/fsurg.2015.00007 Herring, 2010, Off-label prescribing during pregnancy in the UK: an analysis of 18,000 prescriptions in Liverpool Women's Hospital, Int J Pharm Pract, 18, 226, 10.1211/ijpp.18.04.0007 Rolnik, 2017, Aspirin versus placebo in pregnancies at high risk of preterm preeclampsia, N Engl J Med, 377, 613, 10.1056/NEJMoa1704559 Meher, 2016, Antiplatelet therapy before or after 16weeks gestation for preventing preeclampsia: an individual participant data meta-analysis, Am J Obstet Gynecol, 216 Roberge, 2016, The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis, Am J Obstet Gynecol, 216 Roberge, 2016, Prevention of pre-eclampsia by low-molecular-weight heparin in addition to aspirin: a meta-analysis, Ultrasound Obstet Gynecol, 47, 548, 10.1002/uog.15789 Dastjerdi, 2012, Sildenafil citrate and uteroplacental perfusion in fetal growth restriction, J Res Med Sci, 17, 632 Hofmeyr, 2014, Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems, Cochrane Database Syst Rev Bansilal, 2015, Global burden of CVD: focus on secondary prevention of cardiovascular disease, Int J Cardiol, 201, 10.1016/S0167-5273(15)31026-3 Hennekens, 2014, Aspirin in the primary prevention of cardiovascular disease: current knowledge and future research needs, Trends Cardiovasc Med, 24, 360, 10.1016/j.tcm.2014.08.006 Syngelaki, 2016, Metformin versus placebo in obese pregnant women without diabetes mellitus, N Engl J Med, 374, 434, 10.1056/NEJMoa1509819 Costantine, 2016, Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial, Am J Obstet Gynecol, 214, 10.1016/j.ajog.2015.12.038 Lefkou, 2016, Pravastatin improves pregnancy outcomes in obstetric anti phospholipid syndrome refractory to antithrombotic therapy, J Clin Invest, 126, 2933, 10.1172/JCI86957 Onda, 2015, Sofalcone upregulates the nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 pathway, reduces soluble fms-like tyrosine kinase-1, and quenches endothelial dysfunction: potential therapeutic for preeclampsia, Hypertension, 65, 855, 10.1161/HYPERTENSIONAHA.114.04781 Onda, 2017, Proton pump inhibitors decrease soluble fms-like tyrosine kinase-1 and soluble endoglin secretion, decrease hypertension, and rescue endothelial dysfunction, Hypertension, 69, 457, 10.1161/HYPERTENSIONAHA.116.08408 Cluver, 2015, Double blind, randomised, placebo-controlled trial to evaluate the efficacy of esomeprazole to treat early onset pre-eclampsia (PIE Trial): a study protocol, Br Med J Open, 5, 1 Sibai, 2017, Randomized double-blind placebo controlled evaluation of the safety and efficacy of recombinant antithrombin versus placebo in preterm preeclampsia, Am J Obstet Gynecol, 216, 10.1016/j.ajog.2016.11.1048 Myatt, 2015, Preeclampsia: syndrome or disease?, Curr Hypertens Rep, 17, 83, 10.1007/s11906-015-0595-4 Baschat, 2015, First-trimester screening for pre-eclampsia: moving from personalized risk prediction to prevention, Ultrasound Obstet Gynecol, 45, 119, 10.1002/uog.14770 North, 2011, Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort, Br Med J, 342, d1875, 10.1136/bmj.d1875 Sibai, 2011, Evaluation and management of severe pre-eclampsia, Am J Obstet Gynecol, 205, 191, 10.1016/j.ajog.2011.07.017 Lindheimer, 2009, American Society of Hypertension position paper: hypertension in pregnancy, Clin Hypertens (Greenwich), 11, 214, 10.1111/j.1751-7176.2009.00085.x Ilekis, 2016, Placental origins of adverse pregnancy outcomes: potential molecular targets: an executive workshop summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Am J Obstet Gynecol, 215, S1, 10.1016/j.ajog.2016.03.001 Huppertz, 2014, Oxygenation of the placenta and its role in pre-eclampsia, Pregnancy Hypertens, 4, 244 Redman, 2014, IFPA senior award lecture: making sense of preeclampsia — two placental causes for preeclampsia, Placenta, 35, S20, 10.1016/j.placenta.2013.12.008 Thilaganathan, 2017, Placental syndromes: getting to the heart of the matter, Ultrasound Obstet Gynecol, 49, 7, 10.1002/uog.17378 Huppertz, 2008, Placental origins of preeclampsia: challenging the current hypothesis, Hypertension, 51, 970, 10.1161/HYPERTENSIONAHA.107.107607 Roberts, 2009, The two stage model of preeclampsia: variation on the theme, Placenta, 30, S32, 10.1016/j.placenta.2008.11.009 Dekker, 2007, Pre-eclampsia: is the immune maladaptation hypothesis still standing?: an epidemiological update, J Reprod Immunol, 76, 8, 10.1016/j.jri.2007.03.015 Crosley, 2013, Placental invasion, preeclampsia risk and adaptive molecular evolution at the origin of the great apes: evidence from genome-wide analyses, Placenta, 34, 127, 10.1016/j.placenta.2012.12.001 Bruijn, 2013, Genetic variants in pre-eclampsia: a meta-analysis, Hum Reprod Update, 19, 289, 10.1093/humupd/dms060 Duley, 2007, The Magpie Trial: a randomised trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for women at 2years, Br J Obstet Gynaecol, 114, 300 Thadhani, 2010, Inching towards a targeted therapy for preeclampsia, Hypertension, 55, 238, 10.1161/HYPERTENSIONAHA.109.143933 Mehta, 2016, Gene targeting to the uteroplacental circulation of pregnant guinea pigs, Reprod Sci, 23, 1087, 10.1177/1933719116630411 Carr, 2015, VEGF gene transfer to the utero-placental circulation of pregnant sheep to enhance fetal growth, Methods Mol Biol, 1332, 197, 10.1007/978-1-4939-2917-7_15 von Dadelszen, 2015, Moving beyond silos: how do we provide distributed personalized medicine to pregnant women everywhere at scale? Insights from PRE-EMPT, Int J Gynaecol Obstet, 131, S10, 10.1016/j.ijgo.2015.02.008 Haram, 2014, Genetic aspects of preeclampsia and HELLP syndrome, J Pregnancy, 910751, 1, 10.1155/2014/910751 Williams, 2012, The role of genetics in preeclampsia and potential pharmacogenomics intervention, Pharmacogenomics Pers Med, 5, 37, 10.2147/PGPM.S23141 Cnattingius, 2004, Maternal and fetal genetic factors account for most of familial aggregation of preeclampsia: a population-based Swedish cohort study, Am J Med Genet A, 130, 365, 10.1002/ajmg.a.30257 O'Gorman, 2017, Accuracy of competing risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11–13weeks' gestation, Ultrasound Obstet Gynecol, 49, 751, 10.1002/uog.17399 Dijk, 2005, Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family, Nat Genet, 37, 514, 10.1038/ng1541 Salmon, 2011, Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort, PLoS One, 8, 1 Sitras, 2015, Gene expression profile in cardiovascular disease and preeclampsia: a meta-analysis of the transcriptome based on raw data from human studies deposited in gene expression omnibus, Placenta, 36, 170, 10.1016/j.placenta.2014.11.017 Wolfson, 2017, Erythropoietin and soluble erythropoietin receptor: a role for maternal vascular adaptation to high-altitude pregnancy, J Clin Endocrinol Metab, 1, 242, 10.1210/jc.2016-1767 Maynard, 2003, Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia, J Clin Invest, 111, 649, 10.1172/JCI17189 Huppertz, 2013, Placental protein 13 (PP13): a new biological target shifting individualized risk assessment to personalized drug design combating pre-eclampsia, Hum Reprod Update, 19, 391, 10.1093/humupd/dmt003 Than, 1999, Isolation and, sequence analysis of a cDNA encoding human placental tissue protein 13 (PP-13), a new lysophospholipase, homologue of human eosinophil Charcot-Leyden crystal protein, Placenta, 20, 703, 10.1053/plac.1999.0436 Burger, 2004, Placental protein 13 (PP-13): effects on cultured trophoblasts, and its detection in human body fluids in normal and pathological pregnancies, Placenta, 25, 608, 10.1016/j.placenta.2003.12.009 Than, 2004, Functional analyses of placental protein 13/galectin-13, Eur J Biochem, 271, 1065, 10.1111/j.1432-1033.2004.04004.x Than, 2009, A primate subfamily of galectins expressed at the maternal-fetal interface that promote immune cell death, Proc Natl Acad Sci U S A, 16, 9731, 10.1073/pnas.0903568106 Than, 2014, Evolutionary origins of the placental expression of Chromosome 19 cluster galectins and their complex dysregulation in preeclampsia, Placenta, 35, 855, 10.1016/j.placenta.2014.07.015 Freitag, 2013, Interfering with Gal-1–mediated angiogenesis contributes to the pathogenesis of preeclampsia, PNAS, 110, 11451, 10.1073/pnas.1303707110 Orendi, 2010, The choriocarcinoma cell line BeWo: syncytial fusion and expression of syncytium-specific proteins, Reproduction, 140, 759, 10.1530/REP-10-0221 Orendi, 2011, Placental and trophoblastic in vitro models to study preventive and therapeutic agents for preeclampsia, Placenta, 32, S49, 10.1016/j.placenta.2010.11.023 Huppertz, 2008, Longitudinal determination of serum placental protein 13 during development of preeclampsia, Fetal Diagn Ther, 24, 230, 10.1159/000151344 Than, 2008, Placental protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm pre-eclampsia and HELLP syndrome, Virchows Arch, 453, 387, 10.1007/s00428-008-0658-x Sammar, 2011, Placenta-bound and body fluid PP13 and its mRNA in normal pregnancy compared to preeclampsia, HELLP and preterm delivery, Placenta, 32, S30, 10.1016/j.placenta.2010.09.006 Visegrady, 2001, Homology modelling and molecular dynamics studies of human placental tissue protein 13, Protein Eng, 14, 875, 10.1093/protein/14.11.875 Than, 2015, Galectins: double edged swords in the cross-roads of pregnancy complications and female reproductive tract inflammation and neoplasia, J Pathol Transl Med, 49, 181, 10.4132/jptm.2015.02.25 Than, 2011, PP13, maternal ABO blood groups and the risk assessment of pregnancy complications, PLoS One, 6, 10.1371/journal.pone.0021564 Gonen, 2008, Placental protein 13 as an early marker for pre-eclampsia: a prospective longitudinal study, Br J Obstet Gynaecol, 115, 1465, 10.1111/j.1471-0528.2008.01902.x Grimpel, 2011, Effects of calcium, magnesium, low-dose aspirin and low-molecular-weight heparin on the release of PP13 from placental explants, Placenta, 32, S55, 10.1016/j.placenta.2010.11.019 Orendi, 2011, The choriocarcinoma cell line BeWo: syncytial fusion and expression of syncytium-specific proteins, Reproduction, 140, 759, 10.1530/REP-10-0221 Balogh, 2011, Placental protein 13 (PP13/galectin-13) undergoes lipid raft-associated subcellular redistribution in the syncytiotrophoblast in preterm preeclampsia and HELLP syndrome, Am J Obstet Gynecol, 205, 10.1016/j.ajog.2011.03.023 Than, 2014, Placental protein 13 (PP13) — a placental immunoregulatory galectin protecting pregnancy, Front Immunol, 5, 348, 10.3389/fimmu.2014.00348 Nicolaides, 2006, A novel approach to first-trimester screening for early pre-eclampsia combining serum PP-13 and Doppler ultrasound, Ultrasound Obstet Gynecol, 27, 13, 10.1002/uog.2686 Chafetz, 2007, First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction, Am J Obstet Gynecol, 197, 10.1016/j.ajog.2007.02.025 Romero, 2008, First-trimester maternal serum PP13 in the risk assessment for preeclampsia, Am J Obstet Gynecol, 199, 10.1016/j.ajog.2008.01.013 Khalil, 2010, First-trimester markers for the prediction of pre-eclampsia in women with a-priori high risk, Ultrasound Obstet Gynecol, 35, 671 Meiri, 2014, Prediction of preeclampsia by placental protein 13 and background risk factors and its prevention by aspirin, J Perinat Med, 42, 591, 10.1515/jpm-2013-0298 Sekizawa, 2009, PP13 mRNA expression in trophoblasts from preeclamptic placentas, Reprod Sci, 16, 408, 10.1177/1933719108328615 Shimizu, 2009, PP13 mRNA expression in the cellular component of maternal blood as a marker for preeclampsia, Prenat Diagn, 29, 1231, 10.1002/pd.2380 Farina, 2010, Performance of messenger RNAs circulating in maternal blood in the prediction of preeclampsia at 10–14weeks, Am J Obstet Gynecol, 203, 10.1016/j.ajog.2010.07.043 Gebhardt, 2009, A novel exonic variant (221delT) in the LGALS13 gene encoding placental protein 13 (PP13) is associated with preterm labour in a low risk population, J Reprod Immunol, 82, 166, 10.1016/j.jri.2009.07.004 Bruiners, 2008, Promoter variant −98A-C of the LGALS13 gene and pre-eclampsia, 1 Madar-Shapiro, 2017, Predicting the risk to develop preeclampsia (PE) in the first trimester combining promoter variant −98A/C of LGALS13 (placental protein 13), black ethnicity, previous PE, obesity and maternal age, Fetal Diagn Ther, 10.1159/000477933 Sammar, 2014, The role of the carbohydrate recognition domain of placental protein 13 (PP13) in pregnancy evaluated with recombinant PP13 and the Delt221 PP13 variant, Plos One, 9, 10.1371/journal.pone.0102832 Kliman, 2012, Placental protein 13 and decidual zones of necrosis: an immunologic diversion that may be linked to preeclampsia, Reprod Sci, 19, 16, 10.1177/1933719111424445 Gizurarson, 2013, Effects of placental protein 13 on the cardiovascular system in gravid and non-gravid rodents, Fetal Diagn Ther, 33, 257, 10.1159/000345964 Gizurarson, 2016, Placental protein 13 administration to pregnant rats lowers blood pressure and augments fetal growth and venous remodeling, Fetal Diagn Ther, 39, 56, 10.1159/000381914 Drobnjak, 2017, Placental protein 13 (PP13)-induced vasodilation in pregnant and non-pregnant rat arteries occurs via endothelial signaling pathways, Hypertens Pregnancy, 19, 1 Maille, 2016, Mechanism of hydralazine-induced relaxation in resistance arteries during pregnancy: hydralazine induces vasodilation via a prostacyclin pathway, Vascul Pharmacol, 78, 36, 10.1016/j.vph.2015.07.009 Barron, 2010, Effects of pregnancy, hypertension and nitric oxide inhibition on rat uterine artery myogenic reactivity, J Vasc Res, 47, 463, 10.1159/000313874 Osol, 2014, Maternal uterine vascular remodeling during pregnancy, Microcirculation, 21, 38, 10.1111/micc.12080 Grigsby, 2016, Animal models to study placental development and function throughout normal and dysfunctional human pregnancy, Semin Reprod Med, 34, 11, 10.1055/s-0035-1570031 Erlandsson, 2016, Inventory of novel animal models addressing etiology of preeclampsia in the development of new therapeutic/intervention opportunities, Am J Reprod Immunol, 75, 402, 10.1111/aji.12460 Hutten, 1991, Pathogenesis of pregnancy-induced hypertensive disorders. A review of experimental animal models, Clin Exp Hypertens, 10, 287 Hodari, 1967, Chronic uterine ischemia and reversible experimental “toxemia of pregnancy”, Am J Obstet Gynecol, 97, 597, 10.1016/0002-9378(67)90448-6 Longo, 1983, Maternal blood volume and cardiac output during pregnancy: a hypothesis of endocrinologic control, Am J Physiol, 245, R720 Podjarny, 2004, Placental ischemia and resultant phenotype in animal models of preeclampsia, Semin Nephrol, 24, 596, 10.1016/j.semnephrol.2004.07.011 Ogden, 1940, Rise of blood pressure during ischemia of gravid uterus, Proc Soc Exp Biol Med, 43, 49, 10.3181/00379727-43-11091P Brosens, 1964, A study of the spiral arteries of the decidua basalis in normotensive and hypertensive pregnancies, J Obstet Gynaecol Br Commonw, 71, 222, 10.1111/j.1471-0528.1964.tb04270.x Lunell, 1984, Uteroplacental blood flow in pregnancy induced hypertension, Scand J Clin Lab Invest, 44, 28, 10.3109/00365518409085374 Crews, 2000, Decreased endothelium-dependent vascular relaxation during reduction of uterine perfusion pressure in pregnant rats, Hypertension, 35, 71, 10.1161/01.HYP.35.1.367 Alexander, 2001, Endothelin-A receptor blockade attenuates the hypertension in response to chronic reductions in uterine perfusion pressure, Hypertension, 37, 485, 10.1161/01.HYP.37.2.485 Fuller, 2011, Local versus systemic influences on uterine vascular reactivity during pregnancy in the single-horn gravid rat, Reprod Sci, 18, 723, 10.1177/1933719110396700 Colton, 2012, Influence of constriction, wall tension, smooth muscle activation and cellular deformation on rat resistance artery vasodilator reactivity, Cell Physiol Biochem, 29, 883, 10.1159/000178465 Alexander, 2001, Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide, Hypertension, 37, 1191, 10.1161/01.HYP.37.4.1191 Zatz, 1998, Chronic nitric oxide inhibition model six years on, Hypertension, 32, 958, 10.1161/01.HYP.32.6.958 Hefler, 2001, Endothelial-derived nitric oxide and angiotensinogen: Blood pressure and metabolism during mouse pregnancy, Am J Physiol, 280, R174 Baylis, 1992, Adverse interactions between pregnancy and a new model of systemic hypertension produced by chronic blockade of endothelial derived relaxing factor (EDRF) in the rat, Clin Exp Hypertens, 11, 117 Hale, 2011, Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition, Am J Physiol Heart Circ Physiol, 301, H1266, 10.1152/ajpheart.00519.2011 Osol, 2012, Uterine distension differentially affects remodelling and distensibility of the uterine vasculature in non-pregnant rats, Reprod Fertil Dev, 24, 835, 10.1071/RD11208 Osol, 2017, Altered endothelial nitric oxide signaling as a paradigm for maternal vascular maladaptation in preeclampsia, Curr Hypertens Rep, 19, 82, 10.1007/s11906-017-0774-6 van Dijk, 2010, The STOX1 genotype associated with pre-eclampsia leads to a reduction of trophoblast invasion by alpha-T-catenin upregulation, Hum Mol Genet, 19, 2658, 10.1093/hmg/ddq152 van Dijk, 2011, STOX1: key player in trophoblast dysfunction underlying early onset preeclampsia with growth retardation, J Pregnancy, 521826, 1, 10.1155/2011/521826 Iglesias-Platas, 2007, STOX1 is not imprinted and is not likely to be involved in preeclampsia, Nat Genet, 39, 279, 10.1038/ng0307-279 Doridot, 2013, Preeclampsia-like symptoms induced in mice by fetoplacental expression of STOX1 are reversed by aspirin treatment, Hypertension, 61, 662, 10.1161/HYPERTENSIONAHA.111.202994 Rigourd, 2008, STOX1 overexpression in choriocarcinoma cells mimics transcriptional alterations observed in preeclamptic placentas, PLoS One, 3, 10.1371/journal.pone.0003905 Doridot, 2014, Nitroso-redox balance and mitochondrial homeostasis are regulated by STOX1, a pre-eclampsia-associated gene, Antioxid Redox Signal, 21, 819, 10.1089/ars.2013.5661 Vaiman, 2016, Targeting STOX1 in the therapy of preeclampsia, Expert Opin Ther Targets, 20, 1433, 10.1080/14728222.2016.1253682 Robinson, 2010, Hypertension induced by VEGF signaling pathway inhibition: mechanisms and potential use as a biomarker, Semin Nephrol, 30, 591, 10.1016/j.semnephrol.2010.09.007 Klein, 2016, Influence of the sFlt-1/PlGF ratio on clinical decision-making in women with suspected preeclampsia, PLoS One, 11, 10.1371/journal.pone.0156013 Vanditti, 2014, Carbon monoxide prevents hypertension and proteinuria in an adenovirus sFLT-1 preeclampsia in a mouse model, PLoS One, 9 Szalai, 2015, Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice, PLoS One, 10, 10.1371/journal.pone.0119547 Mandalà, 2012, Endothelial-derived hyperpolarization factor (EDHF) contributes to PlGF-induced dilation of mesenteric resistance arteries from pregnant rats, J Vasc Res, 49, 43, 10.1159/000329821 Brown, 2014, Pre-eclampsia in 2014: seven ways to make a difference, Pregnancy Hypertens, 4, 249, 10.1016/j.preghy.2014.11.001 Roberts, 2013, If we know so much about preeclampsia, why haven't we cured the disease?, J Reprod Immunol, 99, 1, 10.1016/j.jri.2013.05.003 Sur Chowdhury, 2016, Elevated levels of total cell-free DNA in maternal serum samples arise from the generation of neutrophil extracellular raps, Fetal Diagn Ther, 40, 263, 10.1159/000444853 Wurtz, 2014, Genetic determinants of on-aspirin platelet reactivity: focus on the influence of PEAR1, PLoS One, 9, 10.1371/journal.pone.0111816 Schweighofer, 2014, Metformin resistance alleles in polycystic ovary syndrome: pattern and association with glucose metabolism, Pharmacogenomics, 15, 305, 10.2217/pgs.13.223 Fellmann, 2017, Cornerstones of CRISPR–Cas in drug discovery and therapy, Nat Rev Drug Discov, 16, 89, 10.1038/nrd.2016.238 Lander, 2016, The heroes of CRISPR, Cell, 164, 18, 10.1016/j.cell.2015.12.041