| Summary: | During pregnancy, uterine vasculature undergoes significant circumferential growth to increase uterine blood flow, vital for the growing feto-placental unit. However, this process is often compromised in conditions like maternal high blood pressure, particularly in preeclampsia (PE), leading to fetal growth impairment. Currently, there is no cure for PE, partly due to the adverse effects of anti-hypertensive drugs on maternal and fetal health. This study aimed to investigate the vasodilator effect of extra virgin olive oil (EVOO) phenols on the reproductive vasculature, potentially benefiting both mother and fetus. Isolated uterine arteries (UAs) from pregnant rats were tested with EVOO phenols in a pressurized myograph. To elucidate the underlying mechanisms, additional experiments were conducted with specific inhibitors: L-NAME/L-NNA (10<sup>−4</sup> M) for nitric oxide synthases, ODQ (10<sup>−5</sup> M) for guanylate cyclase, Verapamil (10<sup>−5</sup> M) for the L-type calcium channel, Ryanodine (10<sup>−5</sup> M) + 2-APB (3 × 10<sup>−5</sup> M) for ryanodine and the inositol triphosphate receptors, respectively, and Paxilline (10<sup>−5</sup> M) for the large-conductance calcium-activated potassium channel. The results indicated that EVOO-phenols activate Ca<sup>2+</sup> signaling pathways, generating nitric oxide, inducing vasodilation via cGMP and BKCa<sup>2+</sup> signals in smooth muscle cells. This study suggests the potential use of EVOO phenols to prevent utero-placental blood flow restriction, offering a promising avenue for managing PE.
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