The pregnant female human angiotensinogen (hAGN) transgenic rat mated with the male human renin (hREN) transgenic rat is a model of preeclampsia (TgA) with increased blood pressure, proteinuria, and placenta alterations of edema and necrosis at late gestation. We studied vascular responses and the role of COX-derived prostanoids in the uterine artery (UA) at early gestation in this model. TgA UA showed lower stretch response, similar smooth muscle α-actin content, and lower collagen content compared with Sprague-Dawley (SD) UA. Vasodilation to acetylcholine was similar in SD and TgA UA (64 ± 8 vs. 75 ± 6% of relaxation, P > 0.05), with an acetylcholine-induced contraction in TgA UA that was abolished by preincubation with indomethacin (78 ± 6 vs. 83 ± 11%, P > 0.05). No differences in the contraction to phenylephrine were observed (159 ± 11 vs. 134 ± 12 %K_MAX, P > 0.05), although in TgA UA this response was greatly affected by preincubation with indomethacin (179 ± 16 vs. 134 ± 9 %K_MAX, P < 0.05, pD₂ 5.92 ± 0.08 vs. 5.85 ± 0.03, P < 0.05). Endothelium-independent vasodilation was lower in TgA UA (92 ± 2 vs. 74 ± 5% preconstricted tone, P < 0.05), and preincubation with indomethacin restored the response to normal values (90 ± 3 vs. 84 ± 3%). Immunostaining showed similar signals for α-actin, COX-2, and eNOS between groups (P > 0.05). Plasma thromboxane levels were similar between groups. In summary, TgA UA displays functional alterations at early gestation before the preeclamptic phenotype is established. Inhibition of COX enzymes normalizes some of the functional defects in the TgA UA. An increased role for COX-derived prostanoids in this model of preeclampsia may contribute to the development of a hypertensive pregnancy.