Functional Changes in the Uterine Artery Precede the Hypertensive Phenotype in a 1 Transgenic Model of Hypertensive Pregnancy

29 The pregnant female human angiotensinogen (hAGN) transgenic rat mated with the male 30 human renin (hREN) transgenic rat (TgA) is a model of preeclampsia with increased blood 31 pressure, proteinuria, and placenta alterations of edema and necrosis at late gestation. We 32 studied vascular responses and the role of COX-derived prostanoids in the uterine artery 33 (UA) at early gestation in this model. TgA UA showed lower stretch response, similar 34 smooth muscle α–actin content and lower collagen content compared to Sprague-Dawley 35 (SD) UA. Vasodilation to acetylcholine was similar in SD and TgA UA (64±8 vs.75±6% of 36 relaxation; p>0.05) with an acetylcholine-induced contraction in TgA UA that was 37 abolished by pre-incubation with indomethacin (78±6 vs. 83±11%, p>0.05). No differences 38 in the contraction to phenylephrine were observed (159±11 vs.134±12 %KMAX, p>0.05), 39 although in TgA UA this response was greatly affected by pre-incubation with indomethacin 40 (179±16 vs.134±9 %KMAX, p<0.05; pD2 5.92±0.08 vs.5.85±0.03, p<0.05). Endothelium41 independent vasodilation was lower in TgA UA (92±2 vs. 74±5 % pre-constricted tone, 42 p<0.05) and pre-incubation with indomethacin restored the response to normal values (90±3 43 vs. 84±3%). Immunostaining showed similar signals for α-actin, COX-2 and eNOS between 44 groups (p>0.05). Plasma thromboxane levels were similar between groups. In summary, 45 TgA UA displays functional alterations at early gestation, before the preeclamptic 46 phenotype is established. Inhibition of COX enzymes normalizes some of the functional 47 defects in the TgA UA. An increased role for COX-derived prostanoids in this model of 48 preeclampsia may contribute to the development of a hypertensive pregnancy. 49 50