Cyclooxygenase-dependent mechanisms mediate in part the anti-dilatory effects of perivascular adipose tissue in uterine arteries from pregnant rats

Uterine perivascular adipose tissue (PVAT) contributes to uterine blood flow regulation in pregnancy, at least in part, due to its effects on uterine artery reactivity. Here, we investigated the effects of uterine PVAT on endothelium-dependent pathways involved in relaxation of main uterine arteries. We hypothesized that uterine PVAT modulates the balance between the contribution of nitric oxide synthase (NOS)- and cyclooxygenase (COX)-dependent pathways to acetylcholine (ACh)-induced relaxation in isolated uterine arteries. Concentration-response curves to ACh (1 nM – 30 µM) were performed on main uterine arteries from pregnant and non-pregnant rats. Arteries were exposed to Krebs-Henseleit solution (control) or PVAT-conditioned media (PVATmedia) in the presence of the following inhibitors: L-NAME (100 µM), indomethacin (COX inhibitor, 10 µM), SC560 (selective COX-1 inhibitor, 1 µM), NS398 (selective COX-2 inhibitor, 1 µM), SQ 29,548 (selective thromboxane receptor (TP) inhibitor, 1 µM). Indomethacin suppressed ACh-induced relaxation in control uterine arteries from pregnant rats (p1.0). In arteries incubated with PVATmedia, the presence of indomethacin increased ACh-induced relaxation, reversing the anti-dilatory effect of PVATmedia. NOS inhibition reduced ACh-induced relaxation in uterine arteries from pregnant rats, and exposure to PVATmedia did not change this effect. Selective inhibition of COX-1 but not COX-2 suppressed relaxation responses to ACh in control arteries. The presence of PVATmedia abolished the effect COX-1 inhibition. Incubation of uterine arteries from pregnant rats with PVATmedia increased production of thromboxane B 2 (TxB 2 , p=0.01). TP inhibition did not have any effect on the anti-dilatory properties of PVATmedia. In conclusion, uterine PVAT releases transferable factors that reduce relaxation responses to ACh via a COX-dependent mechanism in isolated uterine arteries from pregnant rats.