Graduation Date

Spring 5-10-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Integrative Physiology & Molecular Medicine

First Advisor

Ann Anderson Berry

Abstract

Hypertensive disorders of pregnancy (HDP), include chronic hypertension, gestational hypertension, preeclampsia, and eclampsia, which affect approximately 10% of pregnancies worldwide and significantly increases the risk of adverse maternal and fetal health. HDP is characterized by shallow trophoblast invasion, endothelial dysfunction, oxidative stress, mitochondrial dysfunction, and nitrosative stress, yet the underlying molecular mechanisms remain incompletely understood. A key factor in HDP pathophysiology is the dysregulation of nitric oxide (NO) bioavailability, coupled with increased reactive oxygen/nitrosative species (ROS/RNS), driven by inflammation—particularly the pro-inflammatory cytokine TNFɑ. Nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of antioxidant responses, plays a crucial role in mitigating oxidative and nitrosative damage. However, NRF2 activity is often diminished in the placenta of HDP-affected individuals, exacerbating oxidative stress-induced endothelial dysfunction.

Bulk RNA sequencing was used to investigate differential gene expression in hypertensive versus normotensive human placental tissue, while mitochondrial health was assessed through measurements of oxygen consumption rates (OCR). Analysis revealed dysregulation of immune and metabolic pathways in HDP placentas, with notable upregulation of TNFα, lipopolysaccharide (LPS), arginine vasopressin (AVP), and soluble fms-like tyrosine kinase-1 (sFlt-1) signaling pathways. To model these HDP-related insults, we treated human placental explants with TNFα, LPS, AVP, and sFlt-1, all of which resulted in significant reductions in OCR, indicating compromised mitochondrial function.

We explored the antioxidant potential of the omega-3-derived specialized pro-resolving lipid mediator Resolvin D2 (RvD2). RvD2 was found to attenuate TNFα-induced ROS and mitochondrial dysfunction in trophoblasts. Additionally, RvD2 enhanced NRF2 activity and functioned to increase endogenous antioxidant production.

Using single-walled carbon nanotube sensors, we quantified NO levels in explants treated with TNFα, with or without a pretreatment of RvD2. We found that TNFα disrupted NO homeostasis in hypertensive-affected placental explants, whereas RvD2 effectively restored NO levels in the same explants. We further demonstrated that TNFɑ did not alter NO levels in normotensive placental explants.

Collectively, these findings highlight the therapeutic potential of RvD2 in HDP by mitigating ROS/RNS, improving mitochondrial function, and enhancing placental health. Targeting NRF2 activation and redox homeostasis through omega-3-derived lipid mediators may offer a novel strategy to reduce adverse outcomes associated with HDP.

Comments

2025 Copyright, the authors

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