Vasoactive lipid mediators control uterine vascular reactivity at early pregnancy

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Presentation to the International Society for the Study of Hypertension in Pregnancy


Objectives: To investigate the role of COX-derived prostanoids and the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) on uterine vascular control during early pregnancy in a rodent model of preeclampsia.

Methods: The transgenic female rat containing the human angiotensinogen (hAGN) gene mated with the male transgenic containing human renin (hREN) is a model of preeclampsia (TgA). Uterine arteries (UA) were isolated from Sprague–Dawley (SD, n =7) and TgA (n = 9) rats at 7 days of gestation and mounted in a wire myograph (DMT-USA, 620 M). Concentration response curves were performed in control conditions and after preincubation with indomethacin (Indo, 10^-5M), or inhibitors of endocannabinoid hydrolysis: URB597 (FAAH) or JZL184 (MAGL) at 10^-6 M. Data were fitted to a dose response curve, maximal responses were expressed as percent of maximal response to 75mM KCl (% KMAX) and sensitivity as pD2 (pD2 =-Log[EC50]).

Results: Responses to ACh reached similar maximal relaxations (64± 8 vs. 75± 6%, p >0.05), an increased contraction in TgA UA at ACh >10lM was eliminated by Indo. Contraction to Phe was similar in both groups with an inhibitory effect of Indo in TgA UA (p

Conclusions: Blockade of COX enzymes inhibited ACh, Phe and Ang II contractions whereas endogenous AEA and 2-AG reduced TgA UA Ang II contraction. A pro-contractile role of COX-derived mediators and a counteracting role of AEA and 2-AG in the enhanced Ang II contraction in TgA UA are evident before the hypertensive phenotype is established. These interactions may control uterine vascular function in early stages of preeclampsia.

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