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Mechanisms of Circulating Factors in Endothelial Dysfunction in Preeclampsia Open Access


Other title
nitric oxide
uterine artery
Type of item
Degree grantor
University of Alberta
Author or creator
Kao, Cindy K
Supervisor and department
Davidge, Sandra (Obstetrics and Gynecology, Physiology)
Examining committee member and department
Schulz, Jane (Obstetrics and Gynecology)
Plane, Frances (Pharmacology)
Chandra, Sue (Obstetrics and Gynecology)
Mitchell, Peter (Obstetrics and Gynecology)
Medical Sciences-Obstetrics and Gynecology

Date accepted
Graduation date
Master of Science
Degree level
Preeclampsia, defined as new-onset hypertension after 20 weeks of gestation with concurrent proteinuria, is the leading cause of maternal mortality. Preeclampsia is a multi-system disorder with serious maternal and fetal morbidities, which affects 2 – 8% of pregnancies worldwide. Although the exact etiology is unknown, it is believed that defective trophoblast invasion in early pregnancy leads to placental hypoperfusion and local oxidative stress, which triggers the release of circulating factors and induces endothelial dysfunction in the maternal circulation. Previous literature has shown that circulating factors, and especially syncytiotrophoblast extracellular vesicles (STBEVs), from women with preeclampsia impair endothelial function in small resistance arteries. However, there is a still paucity of data on the mechanism(s) behind such findings. The Davidge laboratory has shown that circulating factors from preeclamptic plasma increase oxidative stress in isolated endothelial cells and impair vasodilation in small resistance arteries, via the activation of the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), which is upregulated in preeclampsia. In addition, LOX-1 is a scavenger receptor that binds oxidized low density lipoprotein as well as many other ligands, including cell debris, platelets, and bacteria. Therefore, we are interested in investigating: 1) the mechanism behind which circulating factors affect endothelium-dependent vasodilation, and 2) the effect of STBEVs on the maternal vasculature and whether it acts as a ligand for LOX-1. Using ex vivo myography experiments, we studied vascular responses in pregnant rat uterine arteries incubated with either preeclamptic plasma or STBEVs derived from human placentas in the absence or presence of various pharmacological agents to examine the involvement of reactive oxidative species, nitric oxide, and prostaglandin pathways. We also measured vascular superoxide levels in exposed arteries using dihydroethidium staining. In addition, we examined the vascular expression of nitric oxide synthase isoforms to further understand the role of nitric oxide in preeclamptic plasma-induced endothelial dysfunction. Our studies support that circulating factors from women with preeclampsia lead to endothelial dysfunction by increasing oxidative stress and decreasing nitric oxide bioavailability. Contrary to our hypothesis, rather than reducing prostaglandin vasodilators, we have found that circulating factors contribute to an increase of prostaglandin H synthase dependent vasoconstrictors. We have also shown that, indeed, STBEVs impair endothelial vasodilation via activation of the LOX-1 receptor which is associated with a reduction in nitric oxide contribution. This thesis contributes to our understanding of the pathophysiology behind the role of circulating factors in vascular dysfunction in preeclampsia. We have also identified that LOX-1 contributes to endothelium-dependent impairment associated with STBEVs, which could potentially be reversed and/or prevented by the inhibition of the LOX-1, thereby making it a potential target of treatment.
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