Date of Award

9-15-2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Benoit, Joseph N.

Abstract

The present study was designed to characterize vascular responsiveness and leptin signaling in small mesenteric and uterine arcuate arteries in a rat model of reduced uterine perfusion pressure. The reduced uterine perfusion pressure (RUPP) model was utilized to mimic the underlying pathology of preeclampsia. The uterine arteries and abdominal aortae of pregnant Sprague-Dawley rats were surgically constricted on day 14 of gestation. Systolic blood pressure measurements were obtained before and during pregnancy using a tail cuff measuring system. Weight was measured with each blood pressure evaluation. The rats were euthanized on gestational day 20. Fetal number, fetal weight and placental weight were measured. The small intestine and adjacent mesentery as well as the uterus were removed and arteries dissected free from surrounding tissue. The arteries were then mounted on a small vessel wire myograph for isometric force measurement. Vessels were then challenged with incremental concentrations of phenylephrine, potassium chloride, angiotensin II, acetylcholine, sodium nitroprusside, calcium ionophore and leptin. Western Blot analysis was used to determine leptin signaling in uterine and mesenteric arteries. Systolic blood pressure was increased in the RUPP model compared to control. Fetal weight, fetal number and placental weight were all decreased in the RUPP group, consistent with decreased uterine perfusion. Data suggested a hyperresponsiveness of both small mesenteric and uterine arcuate arteries to vasoconstrictors in the model of preeclampsia. Impaired relaxation of small mesenteric arteries in response to incremental doses of leptin, calcium ionophore and acetylcholine was also evident. A truncated form of leptin receptor, Ob-Ra, was predominant in placenta and vascular tissues. Signaling pathways producing generation of endothelial nitric oxide synthase were altered in the RUPP model, with deficient production of endothelial nitric oxide synthase evident in the uterine arteries. This research provides the first detailed characterization of leptin-related signaling pathways in pregnancy-induced hypertension. The data suggest that alteration in signal transduction pathways favor a hyper-responsive uterine and peripheral vasculature and that these events underlie the pathophysiology of pregnancy-induced hypertension.

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