京都大学 / 新制・課程博士 / 博士(医学) / 甲第24835号 / 医博第5003号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 浅野, 雅秀, 教授 柳田, 素子, 教授 近藤, 玄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This dissertation develops uncertainty quantification methodologies for modeling, response analysis and optimization of diverse dynamical systems. Two distinct application platforms are considered pertaining to engineering dynamics and precision medicine. First, the recently developed Wiener path integral (WPI) technique for determining, accurately and in a computationally efficient manner, the stochastic response of diverse dynamical systems is employed for solving a high-dimensional, nonlinear system of stochastic differential equations governing the dynamics of a representative model of electrostatically coupled micromechanical oscillators. Compared to alternative modeling and solution treatments in the literature, the current development exhibits the following novelties: a) typically adopted linear, or higher-order polynomial, approximations of the nonlinear electrostatic forces are circumvented; and b) stochastic modeling is employed, for the first time, by considering a random excitation component representing the effect of diverse noise sources on the system dynamics. Further, the WPI technique is enhanced and extended based on a Bayesian compressive sampling (CS) treatment. Specifically, sparse expansions for the system response joint PDF are utilized. Next, exploiting the localization capabilities of the WPI technique for direct evaluation of specific PDF points leads to an underdetermined linear system of equations for the expansion coefficients. Furthermore, relying on a Bayesian CS solution formulation yields a posterior distribution for the expansion coefficient vector. In this regard, a significant advantage of the herein-developed methodology relates to the fact that the uncertainty of the response PDF estimates obtained by the WPI technique is quantified. Also, an adaptive scheme is proposed based on the quantified uncertainty of the estimates for the optimal selection of PDF sample points. This yields considerably fewer boundary value problems to be solved as part of the WPI technique, and thus, the associated computational cost is significantly reduced. Second, modeling and analysis of the physiological mechanism of dynamic cerebral autoregulation (DCA) is pursued based on the concept of diffusion maps. Specifically, a state-space description of DCA dynamics is considered based on arterial blood pressure (ABP), cerebral blood flow velocity (CBFV), and their time derivatives. Next, an eigenvalue analysis of the Markov matrix of a random walk on a graph over the dataset domain yields a low-dimensional representation of the intrinsic dynamics. Further dimension reduction is made possible by accounting only for the two most significant eigenvalues. The value of their ratio indicates whether the underlying system is governed by active or hypoactive dynamics, indicating healthy or impaired DCA function, respectively. The reliability of the technique is assessed by considering healthy individuals and patients with unilateral carotid artery stenosis or occlusion. It is shown that the proposed ratio of eigenvalues can be used as a reliable and robust biomarker for assessing how active the intrinsic dynamics of the autoregulation is and for indicating healthy versus impaired DCA function. Further, an alternative joint time-frequency analysis methodology based on generalized harmonic wavelets is utilized for assessing DCA performance in patients with preeclampsia within one week postpartum, which is associated with an increased risk for postpartum maternal cerebrovascular complications. The results are compared with normotensive postpartum individuals and healthy non-pregnant female volunteers and suggest a faster, but less effective response of the cerebral autoregulatory mechanism in the first week postpartum, regardless of preeclampsia diagnosis.

No description available.

The human proteome is exponentially derived from a limited number of genes via alternative splicing, where one gene gives rise to multiple proteins. Alternatively spliced gene products, although crucial for normal physiology, are also linked to an increasing number of pathologies. Consequently, a growing focus is currently being placed on elucidating the extrinsic cues and ensuing signaling mechanisms which direct changes in gene splicing to yield functionally distinct proteins. Of note is the dysregulation of the vascular endothelial growth factor (VEGF) receptor, Flt1 and its soluble splice variants, sFlt1_v1 and sFlt1_v2, in the pregnancy-related disorder, preeclampsia. Preeclampsia is characterized by proteinuria and hypertension and is responsible for almost 600,000 maternal and fetal yearly deaths, worldwide. Here, we examined the impact of endothelial mitogens VEGF and FGF2 (fibroblast growth factor 2), both of which are upregulated in preeclampsia, on Flt1 transcript variants in umbilical vein endothelial cells. We tested the hypothesis that VEGF modulates the expression of Flt1 variants via the signaling kinase Akt and its impact on SR proteins. VEGF was observed to induce expression of overall Flt1 mRNA, principally as variants Flt1 and sFlt1_v1. Conversely, FGF2 induced a shift in splicing toward sFlt1_v2 without significant increase in overall Flt1. Based on inhibitor studies, the VEGF and FGF2 signals were transduced via ERK, but with the involvement of different upstream components. We mapped predicted SR protein binding to Flt1 pre-mRNA and identified two candidate proteins, SRSF2 and SRSF3, that may be involved in VEGF- or FGF2-induced Flt1 pre-mRNA splicing. Examination of SRSF2 and SRSF3 relative mRNA expression levels, following inhibition of VEGF- and FGF2-activated kinases, indicates that FGF2 significantly downregulates SRSF3 mRNA levels via PKC-independent activation of ERK. Additionally, our data suggest that FGF2 may impact Flt1 and sFlt1_v1 via SR protein kinases Akt and SRPK, while conversely regulating sFlt1_v2 levels via Clk. We did not find evidence of VEGF-induced Flt1 variant splicing via SR protein kinase activation or SRSF2 and SRSF3 mRNA levels. Thus, VEGF and FGF2 signals were tranduced via related but distinct mechanisms to differentially influence Flt1 pre-mRNA splicing. These findings implicate VEGF and FGF2 and their related intracellular signaling mechanisms in soluble Flt1 regulation. / Ph. D.

Thesis (MMed)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: OBJECTIVE: The aim of this study was to compare the accuracy of non-invasive brachial blood pressure measurements, using automated and manual devices, to invasive brachial intra-arterial blood pressure measurements in patients with preeclampsia, during acute severe hypertension. STUDY DESIGN: A prospective descriptive cross sectional study was conducted in the Obstetrics Critical Care Unit (OCCU) of Tygerberg Hospital. Pre-eclamptic patients with acute severe hypertension, who required the placement of brachial intra-arterial lines due to failed radial intra-arterial line placement, were included in the study. Both automated oscillometric and blinded manual aneroid sphygmomanometric blood pressures were recorded during hypertensive peaks and after stabilization of BP using intravenous Labetalol or Nepresol. These two noninvasive methods of blood pressure measurements were compared to brachial intraarterial blood pressure measurements. RESULTS: There was weak correlation between manual and intra-arterial SBP (r = 0.27, p = 0.048) for SBP≥160mmHg. The calculated mean difference between manual SBP compared to the intra-arterial SBP in this group was -23.19mmHg (+/- 19.40). There was moderate correlation between automated and intra-arterial SBP (r = 0.69, p < 0.05). The calculated mean difference between automated SBP compared to the intra-arterial SBP in this group was -16.85mmHg (+/- 11.58). CONCLUSION: This study of pre-eclamptic women demonstrated that both non-invasive methods of BP measurement were inaccurate measures of the true systolic intra-arterial BP and significantly underestimated SBP≥160mmHg when compared to brachial intra-arterial measurements. The SBP was also underestimated, to a lesser degree, for mild moderate hypertension. This study also demonstrated that direct invasive BP monitoring using the brachial artery is a safe method for accurate haemodynamic monitoring. We recommend the use of intra-arterial BP monitoring in pre-eclamptic women with acute severe hypertension. Radial arterial cannulation should be used as the first option and the brachial artery should be used if the first option fails. / AFRIKAANSE OPSOMMING: DOELWIT: Die doel van hierdie studie was om die akuraatheid van nie indringende bragiale bloeddruk metings, wat met outomatiese en manuele aparate geneem is, te vergelyk met bragiale intra-arteriele bloeddruk metings gedurend akute erge hipertensie in pasiente met pre-eklampsie, STUDIE ONTWERP: ʼn Prospektiewe beskrywende dwarssnit studie was in die Obstetriese Kritiese Sorg Eenheid (OCCU) van Tygerberg Hospitaal uit gevoer. Preeklamptiese pasiente met akute erge hipertensie, wat bragiale intra-arteriele lyne nodig gehad het, as gevolg van gefaalde radiale intra-arteriele lyn plasing, was in hierdie studie ingesluit. Beide outomatiese ossilometriese en geblinde aneroide sfigmomanometriese bloeddrukke, tydens hipertensiewe pieke en na stabilisering van bloeddrukke met binneaarse Labetalol of Nepresol, was aangeteken, Die twee nie indringende metodes van bloeddruk meting was met bragiale intra-arteriele bloeddruk metings vergelyk. RESULTATE: Daar was ʼn swak korrelasie tussen manuele en intra-arteriele sistoliese bloedrukke SBP (r = 0.27, p = 0.048) vir SBP≥160mmHg. Die berekende gemiddelde verskil tussen manuele SBP en intra-arteriele SBP was -23.19mmHg (+/- 19.40) in hierdie groep. Daar was ʼn matige korrelasie tussen outomatiese en intra-arteriele SBP (r = 0.69, p < 0.05). Die berekende gemiddelde verskil tussen outomaties SBP vergelyk met intra-arteriele SBP was -16.85mmHg (+/- 11.58) in hierdie groep. GEVOLGTREKKING: Hierdie studie van pre-eklamptiese vrouens, het getoon dat beide nie indringende metodes van bloeddruk meting, nie akurate metings van ware sistoliese intraarteriele bloeddruk is nie, en SBP≥160mmHg word aansienlik onderskat wanneer dit met bragiale intra-arteriele metings vergelyk word. Die SBP was ook tot ʼn minder mate onderskat vir matige hipertensie. Die studie het ook getoon dat die direkte bragiale intra-arteriele metode van bloeddruk monitering, ʼn veilige metode van hemodinamiese monitering is. Ons beveel die gebruik van intra-arteriele bloeddruk monitering aan, in preeklamptiese vrouens met akute erge hipertensie. Radiale arteriele kanulasie moet gebruik word as die eerste opsie en die bragiale arterie moet gebruik word as die eerste opsie faal.

Adipositas und die damit verbundenen Begleiterkrankungen zeigen einen deutlichen Anstieg der Prävalenz in der Bevölkerung. Auch für die Schwangerschaft gilt starkes Übergewicht als Risikofaktor für metabolische und vaskuläre Komplikationen wie Gestationsdiabetes mellitus (GDM) und Präeklampsie (PE). In den letzten 20 Jahren wurde eindrücklich nachgewiesen, dass eine Dysregulation von Fettzell-sezernierten Proteinen, sogenannten Adipokinen, ursächlich zu GDM und PE beitragen könnte. Zu Beginn der Dissertation lagen jedoch nur unzureichende Daten über die Regulation des Insulinresistenz-induzierenden, anti-adipogenen und anti-angiogenen Adipokins Preadipocyte factor-1 (Pref-1) bei GDM und PE vor. Die vorliegende Arbeit untersucht daher die Regulation von zirkulierendem Pref-1 bei GDM und PE sowie seine Expression in der Plazenta. Bei 74 Patientinnen mit GDM konnte kein signifikanter Unterschied der Pref-1 Konzentrationen (0.40 µg/l) verglichen zu 74 Gesunden (0.42 µg/l) (p = 0.655) festgestellt werden (Wurst U et al., Cytokine 2015; 71: 161–164). Es zeigte sich in der Kohorte eine unabhängige Assoziation zwischen Pref-1 und Schwangerschaftsalter bei der Blutentnahme, Triglyzeriden, Kreatinin, Body Mass Index und C reaktivem Protein (p < 0.05). In einer Studienkohorte von 51 Schwangeren mit PE wurden signifikant niedrigere Serumspiegel von Pref-1 (0.49 µg/l) im Vergleich zu 51 gesunden Schwangeren (0.68 µg/l) (p < 0.001) gemessen (Schrey S, Wurst U, et al., Cytokine 2015; 75: 338–343). In der multiplen Regressionsanalyse waren PE, Schwangerschaftsalter zum Zeitpunkt der Blutentnahme sowie zirkulierendes Leptin unabhängige Prädiktoren für Pref-1. Im peripartalen Zeitraum zeigte sich ein akuter und deutlicher Abfall von zirkulierendem Pref-1 im mütterlichen Blut und das Adipokin wurde immunhistochemisch im Plazentagewebe nachgewiesen. Die Daten dieser Studien sind vereinbar mit den Hypothesen, dass Pref-1 mit fortschreitender Schwangerschaft zunehmend produziert wird, die Plazenta zur Sekretion des Adipokins aktiv beiträgt sowie das Adipokin bei PE dysreguliert ist. Weiterführende Untersuchungen im Tiermodell sowie prospektive Studien sind notwendig, um die Signifikanz von Pref-1 bei GDM und PE näher zu untersuchen.

Implantation requires complex molecular and cellular events involving coagulation, angiogenesis and immunological processes that need to be well regulated for a pregnancy to establish and progress normally.  The overall aim of this thesis was to study different models associated with atypical angiogenesis, impaired implantation and/or placentation, such as recurrent miscarriage (RM), oocyte donation (OD) and preeclampsia. Histidine-rich glycoprotein (HRG), a serum protein with angiogenic potential has been previously shown to have an impact on implantation and fertility.  In two retrospective case-control studies, women suffering from RM (Study I) and gestational hypertensive disorders (GHD) (Study IV) have been compared to healthy control women, regarding carriership of HRG genotypes (HRG A1042G and C633T SNP, respectively).  According to the findings of this thesis, heterozygous carriers of the HRG A1042G SNP suffer from RM more seldom than homozygous carriers (Study I).  Additionally, the presence of the HRG 633T allele was associated with increased odds of GHD (GHD IV).  Studies II and III comprised a national cohort of relatively young women with optimal health status conceiving singletons with donated oocytes versus autologous oocytes (spontaneously or via IVF).  We explored differences in various obstetric (Study II) and neonatal (Study III) outcomes from the Swedish Medical Birth Register.  Women conceiving with donated oocytes had a higher risk of GHD, induction of labor and cesarean section, as well as postpartum hemorrhage and retained placenta, when compared to autologously conceiving women.  OD infants had higher odds of prematurity and lower birthweight and length when born preterm, compared to neonates from autologous oocytes.  With regard to the indication of OD treatment, higher intervention but neverthelss favourable neonatal outcomes were observed in women with diminished ovarian reserve; the risk of GHD did not differ among OD recipients after adjustment. In conclusion, HRG genetic variation appears to contribute to placental dysfunction disorders.  HRG is potential biomarker that may contribute in the prediction of the individual susceptibility for RM and GHD.  Regarding OD in Sweden, the recipients-despite being of optimal age and health status- need careful preconceptional counselling and closer prenatal monitoring, mainly due to increased prevalence of hypertensive disorders and prematurity.

OBJECTIF: Évaluer le rôle de l’endostatine, un nouveau marqueur anti-angiogénique, pour prédire le risque de prééclampsie (PE). METHODES: Il s’agit d’une étude cas témoins nichée dans deux cohortes prospectives. Les échantillons sanguins étaient collectés entre 11 et 17 semaines puis entre 18 et 26 semaines d’aménorrhée. L’hypertension gestationnelle était définie par une tension artérielle supérieure ou égale à 140/90mmHg à 2 reprises. Les cas de prééclampsie étaient définis par une hypertension gestationnelle associée à une protéinurie supérieure ou égale à 0.3 g /24h après 20 semaines de grossesse. La concentration d’endostatine était mesurée par une technique d’ELISA. Les résultats étaient exprimés en multiples de la médiane (MoM) et ajustés pour l’âge maternel, l’âge gestationnel, l’ethnie, et la cohorte d’origine. Une régression logistique était utilisée pour calculer des odds ratios (OR) ajustés et prédire le risque de PE. RESULTATS: Au total nous avons étudié 77 PE et 150 témoins chez des grossesses uniques. Parmi les PE 21 étaient de survenue précoce, avec un diagnostic avant 34 semaines et 41 étaient des PE sévères. Les cas avaient un IMC plus élevé que les témoins et étaient plus souvent Africaines. Les taux médians d’endostatine étaient significativement plus élevés chez les PE que chez les témoins au 1er trimestre (94.2 versus 90.7 ng/ml, p=0.004) et 2ème trimestre (105.8 versus 99.3 ng/ml p=0.002). Le taux d’endostatine entre 18 et 26 semaines était même plus élevé chez les patientes qui développaient une PE précoce. Lorsque l’endostatine était supérieure au 75èmepercentile (exprimée en MoM), le OR ajusté était de 1.33 95IC [0.68-2.58] à 11-17 semaines et 1.77 [0.94-3.34] à 18-26 semaines. L’OR ajusté pour les PE précoces était 3.51 [1.18-10.43] entre 11-17 semaines et 2.17 [0.67-7.06] entre 18-26 semaines. CONCLUSIONS: Un taux élevé d’endostatine dès le 1er trimestre est associé à une augmentation du risque de PE et surtout d’un risque de prééclampsie précoce. Toutefois l’endostatine seule a une trop faible valeur prédictive pour avoir une utilité clinique. / OBJECTIVE: To evaluate a new anti-angiogenic factor, endostatin, in relation to the risk of preeclampsia (PE). STUDY DESIGN: We performed a case control study nested in two separate prospective cohorts. Serum samples were collected at 11-17 weeks and 18-26 weeks of gestation. Maternal endostatin levels were measured by ELISA. Results were expressed as multiples of the median (MoM) adjusted for maternal age, gestational age, ethnicity, and cohort of origin. Logistic regression was used to calculate adjusted odds ratios (aORs) of PE. RESULTS: A total of 77 PE and 150 controls of singleton pregnancies were studied, including 21 early-onset PE (diagnosis before 34 weeks) and 41 severe PE. Cases had a higher pre-pregnancy BMI and were more likely of African ethnicity than controls. Endostatin levels were significantly higher in women with PE compared to controls at both the first and second trimester (median 94.2 vs. 90.7 ng/ml p=0.004 and 105.8 vs. 99.3 ng/ml p= 0.002 respectively). Endostatin levels were even higher in women with early-onset PE. At a cut-off level of 75th percentile of endostatin MoMs, the adjusted ORs for PE were 1.33, 95CI [0.68-2.58] at 11-17 weeks and 1.77 [0.94-3.34] at 18-26 weeks. The aORs for early-onset PE were 3.51 [1.18-10.43] at 11-17 weeks and 2.17 [0.67-7.06] at 18-26 weeks, respectively. CONCLUSION: Higher endostatin levels as early as in the first trimester may indicate an increased risk of subsequent PE, especially early onset PE. However endostatin alone has a poor predictive value for clinical usefulness.

Determina la utilidad de la flujometría Doppler color en el diagnóstico y manejo de la restricción de crecimiento intrauterino, en embarazadas preeclámpticas en la Clínica “Bolívar” de Babahoyo, Ecuador durante el año 2013. Utiliza una metodología observacional de tipo descriptivo. Analiza una muestra de 96 gestantes de acuerdo a los criterios de inclusión y exclusión. Cuyos resultados en el comparativo entre el año 2008 con el 2013 arrojan que los estados hipertensivos en el embarazo han disminuido 13,4%; y a su vez la razón de mortalidad materna por esa causa. Además, el nivel de restricción de crecimiento intrauterino fue leve 49,5%, moderado 41,7% y severo 9,4%. Concluye que la flujometría Doppler color en la restricción del crecimiento intrauterino en embarazadas preeclámpticas atendidas en la clínica “Bolívar” ha permitido mejorar la actuación diagnóstica y resolutiva del embarazo disminuyendo la morbimortalidad materna y perinatal, corroborando la hipótesis planteada en esta investigación. Se recomienda que la flujometría Doppler se constituye en la herramienta fundamental para evaluar las diferencias y tomar la decisión correcta, espera expectante o interrupción del embarazo. El Doppler permite diferenciar el producto pequeño y sano, del producto con restricción de crecimiento. / Tesis

La prééclampsie est un syndrome pathologique défini chez la femme par l’apparition de novo d’une hypertension artérielle (pression artérielle systolique supérieure à 140 mmHg) et d’une protéinurie (supérieure à 300 mg par jour) au cours de la grossesse. Il s’agit de la deuxième cause de mortalité maternelle en France. Les mécanismes physiopathologiques de ce syndrome, encore mal connus, semblent faire intervenir une dysfonction placentaire à l’origine d’une activation systémique de l’endothélium maternel. Pour améliorer la prise en charge de la prééclampsie et prévenir les complications à court et à long terme, la clé serait d’associer la mise en place d’un dépistage précoce à de nouveaux traitements capables de renverser l’aggravation des symptômes qui, semblerait-il, est inévitable. Notre équipe travaille sur le gène STOX1, exprimé dans les cellules placentaires. Ce gène coderait un facteur de transcription dont jusqu’à présent aucun élément de réponse sur l’ADN n’a été trouvé. Des variants de ce gène ont été identifiés en 2005 chez des patientes atteintes de prééclampsie, et des études cellulaires ont montré que ce facteur est associé au syndrome prééclamptique. Deux modèles d’étude établis et caractérisés au laboratoire ont confirmé l’implication de ce gène dans le syndrome. Notre modèle cellulaire est une lignée de choriocarcinomes surexprimant STOX1. L’équipe a montré en 2008 que les altérations transcriptomiques dues à la surexpression de STOX1 dans cette lignée cellulaire sont corrélées à celles observées dans les placentas de patientes prééclamptiques. Notre modèle murin a été obtenu par transgénèse additive du gène STOX1 humain. Bien que la prééclampsie ne se développe pas spontanément chez les rongeurs, il a été montré en 2013 que des souris femelles sauvages croisées avec des mâles transgéniques développent un phénotype prééclamptique sévère comprenant une hypertension et une protéinurie. Dans le but de mieux comprendre le lien entre la surexpression de STOX1 et l’apparition d’une prééclampsie, nous avons exploré la production in vitro et in vivo de radicaux libres de l’oxygène et de l’azote, molécules constituant de bons candidats pour jouer un rôle pivot dans l’origine des symptômes. Nous avons pu montrer que STOX1 était capable, in vitro et in vivo, de moduler le stress oxydatif, la fonction mitochondriale et la balance des radicaux libres dérivés de l’oxygène et de l’azote. De plus, nous avons étudié dans le modèle murin l’effet de la surexpression de STOX1 dans le placenta sur les organes du système cardiovasculaires. Nous avons pu montrer que des souris femelles sauvages portant des foetus transgéniques subissaient une dysfonction endothéliale associée à une hypertrophie cardiaque pathologique. Enfin, des études en cours de biologie moléculaire in vitro et in silico tentent d’explorer plus finement les fonctions moléculaires et cellulaires de la protéine STOX1, afin de résoudre son rôle dans la prééclampsie, ou dans d’autres domaines de biologie cellulaire. Une partie de ces travaux a notamment permis d’identifier une séquence d’ADN physiquement reconnue par la protéine STOX1. Le travail réalisé au cours de cette thèse permettra d’une part de mieux comprendre la fonction d’une protéine impliquée dans des maladies complexes comme la prééclampsie et la maladie d’Alzheimer, et d’autre part d’aborder de façon plus ciblée la recherche de nouveaux marqueurs ou de nouvelles thérapeutiques pour la prééclampsie grâce au modèle murin. / Preeclampsia is a disease syndrome defined in women by the apparition of a de novo hypertension (systolic blood pressure above 140 mmHg) and proteinuria (greater than 300 mg per day) during pregnancy. This is the second cause of maternal mortality in France. The pathophysiology of this syndrome, still poorly understood, seem to involve placental dysfunction and a systemic activation of the maternal endothelium. To improve the management of preeclampsia and prevent short and long term complications, the key would be to combine the development of early screening and new treatments to reverse the worsening of symptoms which seem inevitable. Our team works on STOX1 gene, expressed in placental cells. This gene would encode a transcription factor for which no responsive element on the DNA has been found so far. Variants of this gene have been identified in 2005 among patients with preeclampsia, and cellular studies have shown that this factor is associated with preeclampsia syndrome. Two study models, established and characterized in the laboratory, confirmed the involvement of this gene in the syndrome. Our cell model is a line of choriocarcinoma overexpressing STOX1. The team showed in 2008 that the transcriptome alterations by STOX1 overexpression in this cell line are correlated with those observed in placentas of preeclamptic patients. Our murine model was obtained by additive transgenesis of the human STOX1 gene. Although preeclampsia does not develop spontaneously in rodents, it was shown in 2013 that wild type female mice mated with transgenic males develop a severe preeclamptic phenotype including hypertension and proteinuria. In order to better understand the link between the overexpression of STOX1 and the onset of preeclampsia, we explored the in vitro and in vivo production of oxygen- and nitrogen-derived free radicals, which are good candidates to play a pivotal role in causing symptoms. We showed that, in vitro and in vivo, STOX1 was able to modulate oxidative stress, mitochondrial function and free radicals balance. In addition, we studied in the mouse model the effect of an overexpression of STOX1 in the placenta on the cardiovascular system. We showed that wild female mice with transgenic fetus underwent an endothelial dysfunction associated with a pathological cardiac hypertrophy. Finally, molecular in vitro and in silico ongoing studies try to explore more precisely the molecular and cellular functions of STOX1 protein to resolve its role in preeclampsia, or in other areas of cell biology. Part of this work enabled the identification of a DNA sequence that is physically recognized by STOX1 protein. The work done during this thesis will help better understand the function of a protein involved in complex diseases such as preeclampsia and Alzheimer's disease. It will also help search for new markers or new treatments for preeclampsia thanks to the mouse model.