Introduction: Preeclampsia is a pregnancy-specific syndrome characterized by new-onset hypertension and systemic vascular dysfunction. Oxidative stress likely plays an intermediary role, but the underlying mechanisms remain unclear. Intriguingly, emerging research underpins a strong interplay between oxidative stress and endoplasmic reticulum (ER) stress, leading to vascular dysfunction. We hypothesize that ER stress is a molecular determinant of oxidative stress contributing to impaired endothelium-dependent relaxation in a model of preeclampsia.
Methods: We used a selective reduced uterine perfusion pressure rat model (sRUPP) for preeclampsia. On gestational day (GD)14, silver clips (100µm) were placed on both ovarian and uterine arteries of pregnant Sprague Dawley rats (sRUPP; n= 5) or on abdominal fat (Sham control; n=5). On GD19, blood pressure was measured using the CODA tail-cuff system. Rats were euthanized on GD20, mesenteric arteries were isolated and endothelium-dependent relaxation (Methylcholine) was assessed in the presence and absence of tauroursodeoxycholic acid (TUDCA; an ER stress inhibitor) using wire myography. P-elF2alpha (an ER stress marker) protein levels were measured in mesenteric arteries using Western blotting.
Results: Fetal weight (p<0.003) and litter size (p<0.001) were decreased in sRUPP compared to controls. sRUPP rats had elevated mean arterial pressures compared to controls (p=0.01). Endothelium-dependent vasodilation was not different between control and sRUPP rats, however, TUDCA tended to decrease sensitivity to methylcholine only in the control animals (pEC50; p=0.08). P-elF2 alpha expression appeared higher in control compared to sRUPP arteries.
Conclusion: Our sRUPP model showed some aspects of preeclampsia, such as lower fetal weight and increased blood pressure. Contrary to our expectations, inhibition of ER stress may impair vasodilation in control arteries. These intriguing data suggest a potential physiological role for ER stress during pregnancy. However, further studies are necessary to confirm these preliminary findings and elucidate mechanisms behind ER stress and vascular function in normal and pathological pregnancies.
Sandra Davidge– Professor, Department of Obstetrics and Gynecology, Women and Children's Health Research Institute, Department of Physiology, University of Alberta
Raven Kirschenman– Technician, Department of Obstetrics and Gynecology, Women and Children's Health Research Institute, University of Alberta
Christy-Lynn Cooke– Assistant Clinical Professor, Department of Obstetrics and Gynecology, Women and Children’s Health Research Institute, University of Alberta
Floor Spaans– Research associate, Department of Obstetrics and Gynecology, Women and Children's Health Research Institute, University of Alberta