[16-OR]: Vasoactive lipid mediators control uterine vascular reactivity at early pregnancy in the transgenic hAGNxhREN rat.

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 7days of gestation and mounted in a wire myograph (DMT-USA, 620M). Concentration response curves were performed in control conditions and after preincubation with indomethacin (Indo, 10(-5)M), 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 >10μM was eliminated by Indo. Contraction to Phe was similar in both groups with an inhibitory effect of Indo in TgA UA (p<0.05). The contraction to Ang II was increased in TgA UA vs. SD, and decreased by Indo (Ang IIMAX 92±7 vs. 109±4; pD2 8.54±0.03 vs. 8.9±0.08, p<0.05). Inhibition of FAAH and MAGL attenuated both Ang II maximal response and sensitivity (Ang IIMAX 76±9, pD2 8.58±0.06, p<0.05; 83±15, 8.65±0.07, p<0.05) in TgA UA.

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.

DISCLOSURES:

V.M. Pulgar: None. L.M. Yamaleyeva: None. J. Varagic: None. C.M. McGee: None. M. Bader: None. R. Dechend: None. A.C. Howlett: None. K. Brosnihan: None.
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