Isabel Hernández

Preeclampsia (PE) is a multifactorial hypertensive disorder unique to pregnancy and a leading cause of maternal and fetal morbidity and mortality worldwide. Its pathogenesis involves placental dysfunction and an exaggerated maternal inflammatory response. Uric acid (UA), traditionally regarded as a marker of renal impairment, is increasingly recognized as an active contributor to the development of PE. Elevated UA levels are associated with oxidative stress, endothelial dysfunction, immune activation, and reduced renal clearance. Clinically, UA is measured in the second and third trimesters to assess disease severity and guide obstetric management, with higher levels correlating with early-onset PE and adverse perinatal outcomes. Its predictive accuracy improves when combined with other clinical and biochemical markers, particularly in low-resource settings. Mechanistically, UA and its monosodium urate crystals can activate the NLRP3 inflammasome, a cytosolic multiprotein complex of the innate immune system. This activation promotes the release of IL-1β and IL-18, exacerbating placental, vascular, and renal inflammation. NLRP3 inflammasome activation has been documented in placental tissues, immune cells, and kidneys of women with PE and is associated with hypertension, proteinuria, and endothelial injury. Experimental studies indicate that targeting UA metabolism or inhibiting NLRP3 activation, using agents such as allopurinol, metformin, or MCC950, can mitigate the clinical and histopathological features of PE. These findings support the dual role of UA as both a biomarker and a potential therapeutic target in the management of the disease.

Oxidative and inflammatory stress, angiogenic imbalance, and endothelial dysfunction are pathophysiological mechanisms occurring in pre-eclampsia (PE) that may persist over time and predispose women to a higher risk of cardiovascular disease (CVD) in the future. However, there is little evidence on the vascular function of women at risk of PE who have not developed the disease. The main objective of this research is to study factors and biomarkers involved in endothelial dysfunction related to oxidative stress, angiogenic disbalance, and inflammation in women at high risk of term PE who do not develop the disease. An observational, analytical, retrospective, and descriptive study was carried out in a selected sample of 68 high-risk and 57 non-risk of term PE participants in the STATIN study (FFIS/2016/02/ST EUDRACT No: 2016-005206-19). A significant increase in mean arterial pressure (MAP) levels and oxidative stress biomarkers (uric acid, homocysteine, and total serum antioxidant capacity) was found. Biomarkers of inflammation (interleukin-6 and growth differentiation factor 15) and endothelial function (asymmetric dimethylarginine) were significantly elevated in the group at risk of pre-eclampsia. A significative dependence relationship was also established between MAP and interleukin-6 and uric acid. These results suggest that women at high risk of term PE may represent pregnancies with pre-existing maternal risk factors for CVD, manifested by the own cardiovascular overload of pregnancy. A better understanding of maternal cardiovascular function in pregnancy would allow the improved prediction of CVD late in life in women.

The objective of this study was to investigate whether the acute haemodynamic effects of angiotensin‐converting enzyme inhibition with captopril could be enhanced by oestrogen administration, and then to evaluate the mechanisms involved in this enhancement. All experiments were performed in 18‐week‐old female spontaneously hypertensive rats arranged in three experimental groups: intact; ovariectomized (OVX); and ovariectomized plus treatment with 17β‐oestradiol (OVX + E₂). These groups were used to evaluate the effects of captopril administration alone, or following bradykinin B2 receptor blockade or nitric oxide synthase inhibition, on a number of haemodynamic parameters (mean arterial pressure, cardiac index, vascular resistance and heart rate). The drop in mean arterial pressure and vascular resistance index in response to captopril was more pronounced in intact and ovariectomized rats treated with 17β‐oestradiol than in ovariectomized animals. Blockade of bradykinin B2 receptors or inhibition of nitric oxide synthesis attenuated the synergy between 17β‐oestradiol and captopril. It is concluded that ovariectomy blunted the blood pressure and vascular resistance index drop observed in intact rats in response to captopril. Treatment with 17β‐oestradiol prevented the blunted response to captopril in ovariectomized rats. Kinins and nitric oxide may be involved in the mechanisms of 17β‐oestradiol potentiation of the haemodynamic effects of captopril.

Objective: The present study evaluated whether estrogen influences the effect of angiotensin-converting enzyme inhibition in preventing the vascular remodeling induced by hypertension and also investigated the signal mechanism involved in that effect. Design: Ten-week-old female spontaneously hypertensive rats were ovariectomized (OVX) and randomly assigned to the groups: untreated OVX and treated with 17β-estradiol (estradiol, 1.5 mg) and/or captopril (5 mg/kg/day). Evolution of systolic blood pressure was determined until 18 weeks. At that time, the heart and mesentery were excised. Structural changes in coronary vessels were quantified by an image analyzer. Inmunoblotting was performed on mesenteric arteries for determination of phosphorylated (ERK1/2). Results: Estradiol treatment enhanced the antihypertensive effect of captopril in OVX rats. Treatment with captopril slightly modified the media cross-sectional area and wall-to-lumen of myocardial arterioles from OVX spontaneously hypertensive rats, whereas coadministration of captopril and estradiol significantly reduced the media cross-sectional area, wall-to-lumen ratio, and perivascular fibrosis in OVX spontaneously hypertensive rats. Captopril alone did not significantly inhibit extracellular signal-regulated kinase 1/2 phosphorylation, whereas coadministration of captopril and estradiol significantly attenuated this parameter. Conclusions: These results indicate that estrogen may enhance the angiotensin-converting enzyme inhibition-mediated improvement of vascular remodeling in hypertension, which may be partly mediated via inhibition of extracellular signal-regulated kinase 1/2.

We investigated the role of oestrogen in the function and structure of the microcirculation of female spontaneously hypertensive rats (SHRs), and evaluated the effect of 17β‐oestradiol on their cardiovascular response to pharmacological agents that block the formation of angiotensin II. Ten‐week‐old SHRs were randomly assigned to the following groups: intact, ovariectomized, and ovariectomized treated with 17β‐oestradiol (1.5 mg delivered over 60 days) and/or captopril (5 mg kg⁻¹ day⁻¹ for 8 weeks). Systolic blood pressure was determined from the time of ovariectomy up to 18 weeks of age, at which time endothelial function and microvascular density in skeletal muscle were evaluated. Both 17β‐oestradiol and captopril prevented development of hypertension in ovariectomized rats. Furthermore, coadministration of both drugs had a greater antihypertensive effect than either one alone. Acetylcholine‐induced vasodilatation was impaired in ovariectomized SHRs, and the response was improved by treatment with 17β‐oestradiol and/or captopril. In addition, 17β‐oestradiol replacement in ovariectomized rats enhanced the effect of captopril on acetylcholine‐induced vasodilatation. Ovariectomized rats also showed lower microvascular density than intact rats, an effect that was prevented by 17β‐oestradiol replacement or captopril treatment and, to a significantly larger extent, by coadministration of both. We concluded that both 17β‐oestradiol and captopril attenuated the development of hypertension and improved the impairment in microvascular density of ovariectomized SHRs. Moreover, when simultaneously administered, oestradiol and captopril had an additive effect on blood pressure and the microvasculature.

Objective: Estrogens may induce cardioprotective effects and prevent neointima formation in response to vascular injury in vivo. The present study evaluated the effect of 17β-estradiol on myocardial arterial remodeling and on vascular mitogen-activated protein kinase expression in experimental hypertension. Design: The experiments were performed in intact female spontaneously hypertensive rats (SHR), in SHR that were ovariectomized at 10 or 25 weeks of age, and in ovariectomized SHR that were supplemented with 17 β-estradiol (OVX + E₂, 1.5 mg every 8 weeks, subcutaneous pellets). Results: At 18 weeks of age, in all myocardial arterioles and small arteries studied, we found significant increases in wall-to-lumen ratio in ovariectomized rats as compared with intact animals. 17β-estradiol significantly reduced the wall-to-lumen ratio in OVX + E₂ rats. Perivascular fibrosis of small coronary arteries was significantly increased by ovariectomy, and this effect was prevented by long-term treatment with 17β-estradiol. Phosphorylated extracellular signal-regulated kinase 1/2 significantly increased in mesenteric arteries from ovariectomized animals and this effect was prevented by 17β-estradiol. Wall-to lumen ratio and perivascular fibrosis were significantly higher in older intact animals at 33 weeks of age. However, neither ovariectomy nor estradiol replacement had any effect on long-term hypertension-induced vascular remodeling. Conclusions: These data suggest that estradiol may exert a beneficial effect by protecting the vasculature from hypertension-induced myocardial arterial remodeling in the early stages of hypertension, but not when chronic alterations are established after a long-term period of hypertension.

In this study, we tested whether estrogen deficiency is associated with oxidative stress and decreased nitric oxide (NO) production, which could be responsible for an increased blood pressure in ovariectomized rats. Hemodynamic studies were performed on conscious, chronically instrumented rats. Chronic estrogen replacement on ovariectomized rats lowered blood pressure ∼13 mmHg, from 119 ± 3 mmHg in ovariectomized rats to 106 ± 3 mmHg in ovariectomized-treated rats; it was also accompanied by an increase in cardiac index and vascular conductance, achieving hemodynamic values similar to those shown by sham-operated rats. N^G-nitro-l-arginine methyl ester administration lowered significantly less the vascular conductance (0.14 ± 0.01 vs. 0.22 ± 0.03 and 0.26 ± 0.01 ml · min⁻¹· mmHg⁻¹/100 g; P < 0.05) in ovariectomized rats than in the sham-operated and estrogen-treated ovariectomized rats, respectively. Estrogen replacement prevented the lower plasma levels of nitrites/nitrates observed in ovariectomized rats. The lower plasma total antioxidant status and reduced thiol groups and the increase in plasma lipoperoxides presented in ovariectomized animals were reestablished with the estrogen treatment. These results show that estrogen administration decreases blood pressure and increases vascular conductance in ovariectomized rats. This effect may be related to an increase in NO synthesis and/or preventing oxidative stress, then improving endothelial function.