title: Mechanism of vascular dysfunction due to circulating factors in women with pre-eclampsia.
abstract: Circulating factors have been proposed to play a major role in the pathophysiology of endothelial dysfunction in pre-eclampsia (PE), which is defined as new-onset hypertension with proteinuria after 20 weeks of gestation. However, the mechanisms leading to altered vascular reactivity remain unclear. We hypothesized that circulating factors lead to endothelial dysfunction by increasing oxidative stress and reducing nitric oxide (NO) and prostaglandin (PG) bioavailability. Pregnant rat uterine and mesenteric arteries were incubated overnight with 3% normotensive (NP) or PE plasma collected from women upon admission to hospital. Responses to methacholine (MCh) were obtained using wire myography to assess endothelial function pathways. Vascular superoxide level was measured via dihydroethidium staining and nitric oxide synthase (NOS) expression via Western blots. PE plasma significantly increased superoxide levels and impaired endothelial dysfunction in uterine arteries (Emax 79.9±5.6% compared with 44.9±6.3%, P=0.0004), which was restored in the presence of oxidant scavengers or PG synthesis inhibition. Uterine artery vasodilation was abolished in the presence of pan-NOS inhibitor (P<0.0001) in both NP- and PE-treated vessels, but inducible nitric oxide synthase (iNOS)-dependent vasodilation was present only in NP-treated arteries. Uterine arteries exposed to PE plasma exhibit an increased endothelial NOS expression and a decreased iNOS expression. PE plasma did not alter endothelial function in mesenteric arteries, suggesting that the effect of circulating factors was vascular-bed-specific. We have shown that circulating factors lead to endothelial dysfunction via altered oxidative stress and vasodilator pathways. The present study contributes to our understanding of the pathophysiology and finding a potential target for intervention in PE.
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2 Women and Children's Health Research Institute, Edmonton, Alberta, Canada, T6G 1C9.
authors.forename: Cindy K
authors.initials: CK
authors.lastname: Kao
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2 Women and Children's Health Research Institute, Edmonton, Alberta, Canada, T6G 1C9.
authors.forename: Jude S
authors.initials: JS
authors.lastname: Morton
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2 Women and Children's Health Research Institute, Edmonton, Alberta, Canada, T6G 1C9.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Quon
authors.affiliation: Women and Children's Health Research Institute, Edmonton, Alberta, Canada, T6G 1C9 Department of Physiology, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Reyes
authors.affiliation: Fundación Oftalmológica de Santander-FOSCAL, Dirección de Investigaciones, Desarrollo e Innovación Tecnológica, Calle 155A N. 23-09, Urbanización El Bosque, Floridablanca, Colombia.
authors.forename: Patricio
authors.initials: P
authors.lastname: Lopez-Jaramillo
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2 Women and Children's Health Research Institute, Edmonton, Alberta, Canada, T6G 1C9 Department of Physiology, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7 Sandra.davidge@ualberta.ca.
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
mesh_terms: D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D011225:Pre-Eclampsia / Q000097:blood* / Q000175:diagnosis / Q000503:physiopathology; D011247:Pregnancy; D011453:Prostaglandins / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D055988:Uterine Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D004791:Enzyme Inhibitors; D011453:Prostaglandins; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat
keywords: circulating factors; endothelium; nitric oxide; pre-eclamptic plasma; prostaglandin; uterine artery