Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, driven by complex interactions among genetic, environmental, and lifestyle factors, with diet playing a pivotal role. Extra Virgin Olive Oil (EVOO), a cornerstone of the Mediterranean diet (MedDiet), is a plant-based fat that has garnered attention for its robust cardiovascular benefits, which are attributed to its unique composition of monounsaturated fatty acids (MUFAs), particularly oleic acid (OA); and bioactive polyphenols, such as Hydroxytyrosol (HT) and oleocanthal. These compounds collectively exert antioxidant, anti-inflammatory, vasodilatory, and lipid-modulating effects. Numerous clinical and preclinical studies have demonstrated that EVOO’s properties reduce major modifiable cardiovascular risk factors, including hypertension, dyslipidemia, obesity, and type 2 diabetes. EVOO also promotes endothelial function by increasing nitric oxide (NO) bioavailability, thus favoring vasodilation, lowering blood pressure (BP), and supporting vascular integrity. Furthermore, it modulates biomarkers of cardiovascular health, such as C-reactive protein, low-density lipoprotein (LDL) cholesterol, and NT-proBNP, aligning with improved hemostatic balance and reduced arterial vulnerability. Emerging evidence highlights its interaction with gut microbiota, further augmenting its cardioprotective effects. This review synthesizes current evidence, elucidating EVOO’s multifaceted mechanisms of action and therapeutic potential. Future directions emphasize the need for advanced extraction techniques, nutraceutical formulations, and personalized dietary recommendations to maximize its health benefits. EVOO represents a valuable addition to dietary strategies aimed at reducing the global burden of cardiovascular diseases.

Increasing levels of estrogens across gestation are partly responsible for the physiological adaptations of the maternal vasculature to pregnancy. The G protein-coupled estrogen receptor (GPER) mediates acute vasorelaxing effects in the uterine vasculature, which may contribute to the regulation of uteroplacental blood flow. The aim of this study was to investigate whether GPER expression and vasorelaxation may occur following pregnancy. Elucidation of the functional signalling involved was also investigated. Radial uterine and third-order mesenteric arteries were isolated from non-pregnant (NP) and pregnant rats (P). GPER mRNA levels were determined and—concentration–response curve to the GPER-specific agonist, G1 (10⁻¹⁰–10⁻⁶ M), was assessed in arteries pre-constricted with phenylephrine. In uterine arteries, GPER mRNA expression was significantly increased and vasorelaxation to G1 was significantly enhanced in P compared with NP rats. Meanwhile, in mesenteric arteries, there was a similar order of magnitude in NP and P rats. Inhibition of L-type calcium channels and extracellular signal-regulated kinases 1/2 significantly reduced vasorelaxation triggered by G1 in uterine arteries. Increased GPER expression and GPER-mediated vasorelaxation are associated with the advancement of gestation in uterine arteries. The modulation of GPER is exclusive to uterine arteries, thus suggesting a physiological contribution of GPER toward the regulation of uteroplacental blood flow during pregnancy.

Placental protein 13 (PP13) exhibits a plasma concentration that increases gradually during normal gestation, a process that is disrupted in preeclampsia, which is characterized by elevated vascular resistance, reduced utero-placental blood flow, and intrauterine growth restriction. This study investigated PP13’s role in vascular tone regulation and its molecular mechanisms. Uterine and subcutaneous arteries, isolated from both pregnant and non-pregnant women, were precontracted with the thromboxane analogue U46619 and exposed to PP13 using pressurized myography. The molecular mechanisms were further investigated, using specific inhibitors for nitric oxide synthase (L-NAME+LNNA at 10⁻⁴ M) and guanylate cyclase (ODQ at 10⁻⁵ M). The results showed that PP13 induced vasodilation in uterine arteries, but not in subcutaneous arteries. Additionally, PP13 counteracted U46619-induced vasoconstriction, which is particularly pronounced in pregnancy. Further investigation revealed that PP13’s mechanism of action is dependent on the activation of the nitric oxide–cGMP pathway. This study provides novel insights into the vasomodulatory effects of PP13 on human uterine arteries, underscoring its potential role in regulating utero-placental blood flow. These findings suggest that PP13 may be a promising candidate for improving utero-placental blood flow in conditions such as preeclampsia. Further research and clinical studies are warranted to validate PP13’s efficacy and safety as a therapeutic agent for managing preeclampsia.

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 (10⁻⁴ M) for nitric oxide synthases, ODQ (10⁻⁵ M) for guanylate cyclase, Verapamil (10⁻⁵ M) for the L-type calcium channel, Ryanodine (10⁻⁵ M) + 2-APB (3 × 10⁻⁵ M) for ryanodine and the inositol triphosphate receptors, respectively, and Paxilline (10⁻⁵ M) for the large-conductance calcium-activated potassium channel. The results indicated that EVOO-phenols activate Ca²⁺ signaling pathways, generating nitric oxide, inducing vasodilation via cGMP and BKCa²⁺ 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.

Placental protein 13 (PP13) exhibits a plasma concentration that increases gradually during normal gestation, a process disrupted in preeclampsia, characterized by elevated vascular resistance, re-duced utero-placental blood flow and intrauterine growth restriction. This study investigated PP13’s role in vascular tone regulation and its molecular mechanisms. Uterine and subcutaneous arteries isolated from both pregnant and non-pregnant women were precontracted with the thromboxane analogue U46619, and exposed to PP13 using pressurized myography. The molecular mechanisms were further investigated using specific inhibitors for ni-tric oxide synthase (L-NAME+LNNA at 10-4 M) and guanylate cyclase (ODQ at 10-5 M). Results showed PP13 induced vasodilation in uterine arteries but not in subcutaneous arteries. Ad-ditionally, PP13 counteract U46619-induced vasoconstriction, which is particularly pronounced in pregnancy. Further investigation revealed that PP13's mechanism of action is dependent on activa-tion of the Nitric oxide-cGMP pathway. This study provides novel insights into the vasomodulatory effects of PP13 on human uterine ar-teries, underscoring its potential role in regulating utero-placental blood flow. These findings suggest PP13 may be a promising candidate for improving utero-placental blood flow in condi-tions such as preeclampsia. Further research and clinical studies are warranted to validate PP13's efficacy and safety as a therapeutic agent for managing preeclampsia.