Date of Completion
Honors College Thesis
Nga Ling (Theresa) Ko, Ph.D.
Alicia Ebert, Ph.D.
preeclampsia, pregnancy, Piezo1, UPBF, NOS, IUGR
Introduction: Women with preeclampsia (PE) and intrauterine growth restriction frequently demonstrate impaired uteroplacental blood flow (UPBF) and inadequate uterine vascular adaptation. Endothelial nitric oxide (NO) mediates arterial vasodilation and expansive remodeling of the maternal uterine vasculature to ensure normal UPBF during gestation. Shear stress secondary to hemochorial placentation, which reduces distal resistance, is the principal physiological stimulus for both NO and remodeling. Knockdown of Piezo1, a shear-stress sensitive cation channel, was shown to inhibit increases in endothelial nitric oxide synthase (eNOS) activity. Using two commonly used rat models of preeclampsia - reduced uteroplacental perfusion pressure (RUPP) model and the in vivo inhibition of nitric oxide synthase (L-NAME) model, we tested the hypothesis that Piezo1 expression and/or functionality is impaired in PE.
Methods: The RUPP surgery was performed on time-pregnant Sprague-Dawley rats (12-14-week-old) at Day 10/22 of gestation (RUPP, n=6). Briefly, the abdominal aorta (below the renal arteries and above the aortic bifurcation) and the uterine arteries of both uterine horns were partially occluded with silver clips to reduce blood flow into the uterine circulation. Pregnant rats with sham surgery (without clips) served as controls (SHAM, n=5). To determine the effect of NOS on Piezo1 functionality in pregnancy, rats (n=6) were given L-NAME in drinking water (0.5 g/L) to inhibit NOS from Day 10 of gestation until euthanasia, with age-matched, normal pregnant rats as control (LP, n=7). Animals were euthanized at late pregnancy (day 20). Main uterine arteries (MUAs) were isolated, pressurized, and assessed in physiological conditions by pressure myography. The functionality of Piezo1 channels was evaluated by Yoda1 (10 and 20 µM), a chemical Piezo1 activator that mimics the effect of fluid shear stress on endothelial cells and induces vasodilation. Segments of MUAs from all groups were also collected for immunofluorescence (IF) staining and Western blot (WB) analysis.
Results:We found that the L-NAME treatment (p
Conclusion: Reduced Yoda1-induced MUA vasodilation in the RUPP and L-NAME treated animals, as well as decreased Piezo1 channel expression in the RUPP animals, indicated that Piezo1 functionality might be impaired by reduced UPBF and reduced NO in PE. These findings suggest that therapeutic interventions targeting Piezo1 signaling may be beneficial for treating PE.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Marasa, Danielle Marie, "The Role of the Piezo1 Channel in Maternal Uterine Circulation During Pregnancy" (2021). UVM Honors College Senior Theses. 418.
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