Elif Kadife

Background: Preeclampsia is a leading cause of maternal and fetal morbidity and mortality, with obesity recognised as a significant risk factor. However, the direct contribution of obesity to the pathophysiology underpinning preeclampsia remains unclear. Objectives: This study aimed to develop and characterise a diet-induced obese mouse model with superimposed preeclampsia to better understand the impact of obesity on disease pathogenesis. Methods: Female mice were fed either standard rodent chow or a high-fat diet from weaning. At 8 weeks of age, mice were mated. Pregnant mice were treated with L-N^G-Nitro arginine methyl ester (L-NAME; to block nitric oxide production) from gestational day (D)7.5 to D17.5 to induce a preeclampsia-like phenotype. Blood pressure was measured on D14.5 and D17.5, followed by the collection of maternal and fetal tissues for histological, biochemical, and molecular analyses. Results: Obese dams exhibited significantly increased body, fat pad, and liver weights compared to lean controls. While L-NAME induced hypertension in the control mice, contrary to expectations, the L-NAME-induced hypertension was partially attenuated in obese dams, with significantly lower systolic and diastolic blood pressures at D14.5 and reduced systolic pressure at D17.5. Fetal weights were comparable between groups, however, placentas were significantly heavier with obesity. Endothelial function, inflammatory markers, and renal gene expression patterns suggested distinct physiological adaptations in obese preeclamptic-like mice. Conclusions: These findings challenge the prevailing assumption that obesity drives hypertension, endothelial dysfunction, and inflammatory markers. The differential vascular and physiological responses observed in the obese dams highlight the complexity of obesity–preeclampsia interactions and underscore the need for refined preclinical models to disentangle mechanistic contributions. This work has implications for personalised management strategies and targeted therapeutic interventions in obese pregnancies at risk of preeclampsia.

Intrauterine growth restriction (IUGR), predominantly caused by placental insufficiency, affects partitioning of nutrients to the fetus. The system A sodium-coupled transporters (SNAT or SLC38), of types A1, A2, and A4, control non-essential amino acid uptake and supply. Here, we aimed to investigate the expression of these transporters across different placental disease cohorts and cells. To determine disease impact, transporter expressions at the gene (qPCR) and protein (western blots) level were assessed in gestationally matched placental tissues. Early (<34 weeks), and late (34–36 weeks) onset IUGR cases with/out preeclampsia were compared to preterm controls. We also investigated level of transporter expression in primary trophoblasts under glucose deprivation (n = 6) and hypoxia conditions (n = 7). SLC38A4 protein was significantly downregulated in early preterm pregnancies complicated with IUGR with/out preeclampsia. There were no differences in late preterm IUGR cohorts. Furthermore, we demonstrate for the first time in primary trophoblast cells, that gene expression of the transporters was sensitive to and induced by glucose starvation. SLC38A4 mRNA expression was also significantly upregulated in response to hypoxia. Thus, SLC38A4 expression was persistently low in early preterm IUGR pregnancies, regardless of disease aetiology. This suggests that gestational age at delivery, and consequently IUGR severity, may influence loss of its expression.

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.