Vasoactive lipid mediators control uterine vascular reactivity at early pregnancy
Date of Publication
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.
Pulgar, V. M.; Yamaleyeva, L. M.; Varagic, J.; McGee, C. M.; Bader, M.; Dechend, R.; Howlett, A. C.; and Brosnihan, K. B., "Vasoactive lipid mediators control uterine vascular reactivity at early pregnancy" (2014). Pharmaceutical Sciences. 2155.