Investigating the Impact of Maternal Obesity on Disease Severity in a Mouse Model of Preeclampsia
Natalie K Binder1, Natasha de Alwis1, Bianca R Fato1
1Therapeutics Discovery & Vascular Function in Pregnancy Group, University of Melbourne, Mercy Hospital for Women, Heidelberg 3084, Australia.
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-NG-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.
