Uncoupled endothelial nitric oxide synthase and oxidative stress in a rat model of pregnancy-induced hypertension.
BACKGROUND
Preeclampsia is a human pregnancy-associated syndrome associated with hypertension, proteinuria, and endothelial dysfunction. We tested whether increased reactive oxygen species (superoxide and peroxynitrite) production and decreased bioavailability of the endothelial nitric oxide (NO) synthase (eNOS) cofactor tetrahydrobiopterin (BH4) contributes to maternal endothelial dysfunction in rats with pregnancy-induced hypertension and several characteristics of preeclampsia.


METHODS
Nonpregnant (DS) and pregnant (PDS) rats were treated with deoxycorticosterone acetate and 0.9% saline for approximately 3 weeks and nonpregnant (Con) and pregnant (P) rats received tap water. Blood pressure, urinary protein levels, mesenteric vascular reactivity, aortic protein expression, and aortic reactive oxygen species levels were compared between the four groups.


RESULTS
The PDS rats had significantly decreased mesenteric endothelium-dependent relaxation responses and aortic NO production compared to Con, DS, and P rats despite increased aortic eNOS expression. Aortic superoxide and peroxynitrite levels were increased in PDS rats compared with Con, DS, and P rats. Scavenging of reactive oxygen species or increasing tetrahydrobiopterin levels normalized mesenteric endothelium-dependent relaxation responses, aortic NO production, and aortic superoxide and peroxynitrite levels in PDS rats.


CONCLUSIONS
These data suggest that increased superoxide production by NADPH oxidase, peroxynitrite degradation of BH4, and uncoupled eNOS contribute to endothelial dysfunction in a rat model of pregnancy-induced hypertension.
Mitchell
Brett M
BM
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA. bmitchell@tamhsc.edu
Cook
Leslie G
LG
Danchuk
Svitlana
S
Puschett
Jules B
JB
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001682:Biological Availability; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000175:diagnosis; D046110:Hypertension, Pregnancy-Induced / Q000209:etiology* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress; D011247:Pregnancy; D011507:Proteinuria / Q000175:diagnosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
D017382:Reactive Oxygen Species; D001708:Biopterins; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; C003402:sapropterin