Abstract P224: Cyclooxygenase-dependent Mechanisms Mediate In Part The Anti-dilatory Effects Of Uterine Perivascular Adipose Tissue In Rat Pregnancy

Abstract

Introduction: Uterine perivascular adipose tissue (PVAT) contributes to uterine blood flow regulation in pregnancy, at least in part, due to its effects on uterine artery tone. We hypothesized that the anti-dilatory effects of uterine PVAT are mediated by vascular nitric oxide synthase (NOS)- and cyclooxygenase (COX)-dependent mechanisms. Methods: Main uterine arteries from pregnant and non-pregnant rats were mounted onto a wire myograph. Concentration-response curves to acetylcholine (ACh, 10 -9 - 3x10 -5 M) were performed on arteries exposed to physiological salt solution or PVAT-conditioned media (PVAT media ) in the presence of the following inhibitors: a) L-NAME (NOS inhibitor, 100 μM), b) indomethacin (COX inhibitor, 10 μM), c) SC560 (COX-1 inhibitor, 1 μM), d) NS398 (COX-2 inhibitor, 1 μM)]. Results: NOS inhibition abolished ACh-induced relaxation in uterine arteries from pregnant rats and exposure to PVAT media did not change this effect [AUC, (-)PVAT media : 244.6 ± 18.1 vs. (-)PVAT media /(+)L-NAME: 52.64 ± 7.4, p < 0.0001; (+)PVAT media : 202.4 ± 15.5 vs. (+)PVAT media /(+)L-NAME: 56.17 ± 11.3, p < 0.0001]. Indomethacin suppressed ACh-induced relaxation in uterine arteries from pregnant rats [AUC, (-)PVAT media : 243.6 ± 6.6 vs. (-)PVAT media /(+)Indomethacin: 123.6 ± 12.3, p < 0.0001] but not in non-pregnant rats (p>1.0). In arteries incubated with PVAT media , the presence of indomethacin increased ACh-induced relaxation [AUC, (+)PVAT media : 125.2 ± 11.4 vs. (+)PVAT media /(+)Indomethacin: 179.1 ± 14.7, p = 0.01]. COX-1 but not COX-2 inhibition suppressed relaxation responses to ACh [AUC, COX-1 inhibition, (-)PVAT media : 244.6 ± 12.0 vs. (-)PVAT media /(+)SC560: 142.4 ± 15.4, p = 0.02; COX-2 inhibition, (-)PVAT media vs. (-)PVAT media /(+)NS398, p=0.1). The anti-dilatory effects of PVAT were not observed in the presence of SC560 or NS398 (p>0.05). Exposure to PVAT media increased the protein content of COX-1 (p=0.05) and COX-2 (p=0.03) and the production of thromboxane B 2 (p=0.01) in uterine arteries from pregnant rats. Conclusion: The anti-dilatory effects of PVAT-derived factors on uterine arteries are mediated in part by COX-derived products and this mechanism is specific to pregnancy.