Laura M. Reyes

Effect of resveratrol on metabolic and cardiovascular function in male and female adult offspring exposed to prenatal hypoxia and a high‐fat diet

Prenatal hypoxia, a common outcome of many pregnancy complications, predisposes offspring to chronic diseases in later life. We investigated the effect of prenatal hypoxia, on a background of a high‐fat diet, on metabolic and cardiac function in adult male and female rat offspring. We also examined the therapeutic role of resveratrol supplementation in preventing metabolic and cardiac dysfunction. Prenatal hypoxia impaired both metabolic and cardiac function in male and only cardiac function in female rat offspring. We also observed that male rat offspring were more susceptible to metabolic and cardiac dysfunction as compared with their female counterparts; this provides evidence of sexual dichotomy in the fetal programming of diseases due to prenatal hypoxia. Resveratrol supplementation in the diet improved metabolic and cardiac function independent of sex; this provides evidence of a possible therapeutic role of resveratrol in susceptible male and female rat offspring exposed to prenatal hypoxia.

Clinical trial to assess the effect of physical exercise on endothelial function and insulin resistance in pregnant women.

BackgroundPreeclampsia (PE) is a common maternal disease that complicates 5 to 10% of pregnancies and remains as the major cause of maternal and neonatal mortality. Cost-effective interventions aimed at preventing the development of preeclampsia are urgently needed. However, the pathogenesis of PE is not well known. Multiple mechanisms such as oxidative stress, endothelial dysfunction and insulin resistance may contribute to its development. Regular aerobic exercise recovers endothelial function; improves insulin resistance and decreases oxidative stress. Therefore the purpose of this clinical trial is to determine the effect of regular aerobic exercise on endothelial function, on insulin resistance and on pregnancy outcome.Methods and design64 pregnant women will be included in a blind, randomized clinical trial, and parallel assignment. The exercise group will do regular aerobic physical exercise: walking (10 minutes), aerobic exercise (30 minutes), stretching (10 minutes) and relaxation exercise (10 minutes) in three sessions per week. Control group will do the activities of daily living (bathing, dressing, eating, and walking) without counselling from a physical therapist.Trial registrationNCT00741312.

Risk factors for preeclampsia in women from Colombia: a case-control study.

Background Preeclampsia (PE) is a multi-causal disease characterized by the development of hypertension and proteinuria in the second half of pregnancy. Multiple risk factors have been associated with the development of PE. Moreover, it is known that these risk factors vary between populations from developed and developing countries. The aim of this study is to identify which risk factors are associated with the development of preeclampsia (PE) among Colombian women. Methods A multi-centre case-control study was conducted between September 2006 and July 2009 in six Colombian cities. Cases included women with PE (n = 201); controls were aged-matched pregnant women (n = 201) without cardiovascular or endocrine diseases for a case-control ratio of 1∶1. A complete medical chart, physical examination and biochemical analysis were completed before delivery. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) of potential risk factors associated with PE. Results The presence of factors present in the metabolic syndrome cluster such as body mass index >31 Kg/m2 (OR = 2.18; 1.14–4.14 95% CI), high-density lipoprotein <1.24 mmol/L (OR = 2.42; 1.53–3.84 95% CI), triglycerides >3.24 mmol/L (OR = 1.60; 1.04–2.48 95% CI) and glycemia >4.9 mmol/L (OR = 2.66; 1.47–4.81 95%CI) as well as being primigravidae (OR = 1.71; 1.07–2.73 95% CI) were associated with the development of PE, after adjusting for other variables. Conclusion Factors present in the cluster of metabolic syndrome and primigravidity were associated with a greater risk of PE among Colombian women. Understanding the role of this cluster of risk factors in the development of PE is of crucial importance to prevent PE and remains to be determined.

Nutritional status among women with pre-eclampsia and healthy pregnant and non-pregnant women in a Latin American country.

Aims:  Pre‐eclampsia (PE) is one of the leading causes of maternal and perinatal morbidity and mortality worldwide. It has been proposed that, among other risk factors, the nutritional status of women can lead to the endothelial dysfunction that characterizes this entity. The aim of the present study was to compare the nutritional status of women with PE with healthy pregnant and non‐pregnant women.

Angiogenic imbalance and plasma lipid alterations in women with preeclampsia from a developing country

Background: An imbalance between anti-angiogenic factors (e.g. soluble vascular endothelial growth factor receptor-1 (s-FLT1) and soluble endoglin (s-Eng)) and pro-angiogenic factors (e.g. placental growth factor (PlGF)) as well as increased oxidized low-density lipoprotein (ox-LDL) concentrations have been associated with preeclampsia (PE). Risk factors associated with the development of PE, however, are known to be different between developed and developing countries. The aim of the study was to determine the levels of s-FLT1, s-Eng, PIGF, and ox-LDL in women with PE from a developing country. Methods: A multi-center case–control study was conducted. One hundred and forty three women with PE were matched by age and parity with 143 healthy pregnant women without cardiovascular or endocrine diseases. Before delivery, blood samples were taken and serum was stored until analysis. Results: Women with PE had lower concentrations of PIGF (p < 0.0001) and higher concentrations of s-Eng (p = 0.001) than healthy pregnant women. There were no differences between the groups regarding ox-LDL or s-FLT1. Women with early onset PE had higher s-FLT1 concentrations (p = 0.0004) and lower PIGF concentrations (p < 0.0001) than their healthy pregnant controls. Women with late onset PE had higher concentrations of s-Eng (p = 0.005). Women with severe PE had higher concentrations of s-Eng (p = 0.0008) and ox-LDL (p = 0.01), and lower concentrations of PIGF (p < 0.0001). Conclusions: Women with PE from a developing country demonstrated an angiogenic imbalance and an increased rate of LDL oxidation. Findings from this study support the theory that PE is a multifactorial disease, and understanding differences in these subpopulations may provide a better target to approach future therapies.

Mechanism of vascular dysfunction due to circulating factors in women with pre-eclampsia.

Circulating factors have been proposed to play a major role in the pathophysiology of endothelial dysfunction in pre-eclampsia (PE), which is defined as new-onset hypertension with proteinuria after 20 weeks of gestation. However, the mechanisms leading to altered vascular reactivity remain unclear. We hypothesized that circulating factors lead to endothelial dysfunction by increasing oxidative stress and reducing nitric oxide (NO) and prostaglandin (PG) bioavailability. Pregnant rat uterine and mesenteric arteries were incubated overnight with 3% normotensive (NP) or PE plasma collected from women upon admission to hospital. Responses to methacholine (MCh) were obtained using wire myography to assess endothelial function pathways. Vascular superoxide level was measured via dihydroethidium staining and nitric oxide synthase (NOS) expression via Western blots. PE plasma significantly increased superoxide levels and impaired endothelial dysfunction in uterine arteries (Emax 79.9±5.6% compared with 44.9±6.3%, P=0.0004), which was restored in the presence of oxidant scavengers or PG synthesis inhibition. Uterine artery vasodilation was abolished in the presence of pan-NOS inhibitor (P<0.0001) in both NP- and PE-treated vessels, but inducible nitric oxide synthase (iNOS)-dependent vasodilation was present only in NP-treated arteries. Uterine arteries exposed to PE plasma exhibit an increased endothelial NOS expression and a decreased iNOS expression. PE plasma did not alter endothelial function in mesenteric arteries, suggesting that the effect of circulating factors was vascular-bed-specific. We have shown that circulating factors lead to endothelial dysfunction via altered oxidative stress and vasodilator pathways. The present study contributes to our understanding of the pathophysiology and finding a potential target for intervention in PE.

Vascular effects of aerobic exercise training in rat adult offspring exposed to hypoxia‐induced intrauterine growth restriction

Prenatal hypoxia, one of the most common consequences of complicated pregnancies, leads to intrauterine growth restriction (IUGR) and impairs later‐life endothelium‐dependent vascular function. Early interventions are needed to ultimately reduce later‐life risk for cardiovascular disease. Aerobic exercise training has been shown to prevent cardiovascular diseases. Whether exercise can be used as an intervention to reverse the vascular phenotype of this susceptible population is unknown. Aerobic exercise training enhanced endothelium‐derived hyperpolarization‐mediated vasodilatation in gastrocnemius muscle arteries in male IUGR offspring, and did not improve nitric oxide‐mediated vasodilatation in IUGR offspring. Understanding the mechanisms by which exercise impacts the cardiovascular system in a susceptible population and the consideration of sexual dimorphism is essential to define whether exercise could be used as a preventive strategy in this population.

Aerobic exercise training reduces cardiac function in adult male offspring exposed to prenatal hypoxia

Intrauterine growth restriction (IUGR) has been associated with increased susceptibility to myocardial ischemia-reperfusion (I/R) injury. Exercise is an effective preventive intervention for cardiovascular diseases; however, it may be detrimental in conditions of compromised health. The aim of this study was to determine whether exercise training can improve cardiac performance after I/R injury in IUGR offspring. We used a hypoxia-induced IUGR model by exposing pregnant Sprague-Dawley rats to 21% oxygen (control) or hypoxic (11% oxygen; IUGR) conditions from gestational day 15 to 21. At 10 wk of age, offspring were randomized to a sedentary group or to a 6-wk exercise protocol. Transthoracic echocardiography assessments were performed after 6 wk. Twenty-four hours after the last bout of exercise, ex vivo cardiac function was determined using a working heart preparation. With exercise training, there was improved baseline cardiac performance in male control offspring but a reduced baseline cardiac performance in male IUGR exercised offspring (P < 0.05). In male offspring, exercise decreased superoxide generation in control offspring, while in IUGR offspring, it had the polar opposite effect (interaction P ≤ 0.05). There was no effect of IUGR or exercise on cardiac function in female offspring. In conclusion, in male IUGR offspring, exercise may be a secondary stressor on cardiac function. A reduction in cardiac performance along with an increase in superoxide production in response to exercise was observed in this susceptible group.

Prenatal Hypoxia Is Associated with Long-Term Retinal Dysfunction in Rats

Background Intra-uterine growth restriction (IUGR) has been associated with increased predisposition to age-related complications. We tested the hypothesis that rat offspring models of IUGR would exhibit exacerbated, age-related retinal dysfunction. Methods Female Sprague-Dawley rats (maintained at 11.5% O2 from gestational day 15 to 21 to induce IUGR) and control offspring (maintained at 21% O2 throughout pregnancy) had retinal function assessed at 2 months (young) and 14 months of age (aged) with electroretinogram (ERG) recordings. Retinal anatomy was assessed by immunofluorescence. Results Deficits in rod-driven retina function were observed in aged IUGR offspring, as evidenced by reduced amplitudes of dark-adapted mixed a-wave Vmax (by 49.3%, P<0.01), b-wave Vmax (by 42.1%, P<0.001) and dark-adapted peak oscillatory potentials (by 42.3%, P<0.01). In contrast to the rod-driven defects specific to aged IUGR offspring, light adapted ERG recordings revealed cone defects in young animals, that were stationary until old age. At 2 months, IUGR offspring had amplitude reductions for both b-wave (Vmax by 46%, P<0.01) and peak oscillatory potential (Vmax by 38%, P<0.05). Finally, defects in cone-driven responses were further confirmed by reduced maximal photopic flicker amplitudes at 2 (by 42%, P<0.001) and 14 months (by 34%, P = 0.06) and critical flicker fusion frequencies at 14 months (Control: 42±1 Hz, IUGR: 35±2 Hz, P<0.05). These functional changes were not paralleled by anatomical losses in IUGR offspring retinas. Conclusions These data support that the developing retina is sensitive to stressors, and that pathways governing cone- and rod-driven function differ in their susceptibilities. In the case of prenatal hypoxia, cone- and rod-driven dysfunction manifest at young and old ages, respectively. We must, therefore, take into account the specific impact that fetal programming might exert on age-related retinal dystrophies when considering related diagnoses and therapeutic applications.

Exercise as a therapeutic intervention to optimize fetal weight

&NA; The Developmental Origins of Health and Disease suggest the in utero environment programs offspring obesity and cardiovascular disease. Therefore, there is a need to implement safe therapeutic interventions that do not involve the intake of medications or biological products during pregnancy that can improve maternal and fetal health. Prenatal exercise is established to promote maternal and fetal health. It is generally recommended that women accumulate at least 150 min per week of moderate‐intensity exercise. It has been demonstrated that prenatal exercise maintains healthy weight gain and improves maternal glucose control, maternal cardiac autonomic control, placental efficiency (increases angiogenesis, downregulates genes involved in fatty acid transport and insulin transport across the placenta, and upregulates genes involved in amino acid transport across the placenta), and oxidative stress. These adaptations following exercise improve maternal metabolism and provide adequate uteroplacental perfusion. In this review, we will focus on exercise as a therapeutic intervention to optimize fetal weight. It has been established that prenatal exercise does not increase the risk of having a small for gestational age baby. To the contrary, prenatal exercise has been associated with the prevention of excessive fat accumulation in the newborn and the maintenance of fetal muscle mass. Graphical abstract Figure. No caption available.