RESUMEN
AIM: Underlying mechanisms of poor pregnancy outcome in obese (OB) mothers (body mass index [BMI] ≥ 30 kg/m2 ) are unknown. Our studies demonstrate that OB pregnant women have altered myometrial artery (MA) function related to the thromboxane and nitric oxide pathways. In obesity, increased central fat mass is associated with an altered endocrine milieu. We tested the hypothesis that in OB pregnant women the omentum, a central fat store, releases factors that promote dysfunction in normal MAs. METHODS: Myometrial and omental adipose tissue biopsies were obtained from women with uncomplicated term pregnancies. Omental adipose tissue explants from six normal weight (NW; BMI 18.5-24.9 kg/m2 ) and six OB (BMI ≥ 30 kg/m2 ) women were cultured and the conditioned medium collected and pooled to produce NW medium and OB medium. Adipokine concentrations were measured using enzyme-linked immunosorbent assays. Wire myography was used to assess the effect of conditioned medium (NW or OB; N = 7) or leptin (100 nM; N = 5) exposure on MA responses to U46619 (thromboxane-mimetic) and bradykinin (endothelial-dependent vasodilator). RESULTS: OB medium had higher leptin and lower adiponectin levels than NW medium. U46619 and bradykinin concentration response curves shifted upwards in MAs exposed to OB medium but were unaffected by leptin. CONCLUSIONS: Omental adipose tissue from OB pregnant women produced altered concentrations of adipokines. Acute OB medium exposure induced MA dysfunction, an effect not mirrored by exposure to leptin. These data suggest that an aberrant endocrine environment created by increased central adiposity in OB pregnant women induces vascular endothelial dysregulation, which may predispose them to a poor pregnancy outcome.
Asunto(s)
Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Leptina/metabolismo , Miometrio/irrigación sanguínea , Miometrio/metabolismo , Obesidad/metabolismo , Epiplón/metabolismo , Complicaciones del Embarazo/metabolismo , Células Cultivadas , Femenino , Humanos , Embarazo , Adulto JovenRESUMEN
Obese women (body mass index ≥30 kg/m(2)) are at greater risk than normal weight women of pregnancy complications associated with maternal and infant morbidity, particularly the development of cardiovascular disease and metabolic disorders in later life; why this occurs is unknown. Nonpregnant, obese individuals exhibit systemic vascular endothelial dysfunction. We tested the hypothesis that obese pregnant women have altered myometrial arterial function compared to pregnant women of normal (18-24 kg/m(2)) and overweight (25-29 kg/m(2)) body mass index. Responses to vasoconstrictors, U46619 (thromboxane mimetic) and arginine vasopressin, and vasodilators, bradykinin and the nitric oxide donor sodium nitroprusside, were assessed by wire myography in myometrial arteries from normal weight (n = 18), overweight (n = 18), and obese (n = 20) women with uncomplicated pregnancies. Thromboxane-prostanoid receptor expression was assessed using immunostaining in myometrial arteries of normal weight and obese women. Vasoconstriction and vasodilatation were impaired in myometrial arteries from obese women with otherwise uncomplicated pregnancies. Disparate agonist responses suggest that vascular function in obese women is not globally dysregulated but may be specific to thromboxane and nitric oxide pathways. Because obesity rates are escalating, it is important to identify the mechanisms underlying impaired vascular function and establish why some obese women compensate for vascular dysfunction and some do not. Future studies are needed to determine whether central adiposity results in an altered endocrine milieu that may promote vascular dysfunction by altering the function of perivascular adipose tissue.
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Arterias/fisiopatología , Miometrio/irrigación sanguínea , Obesidad/fisiopatología , Transducción de Señal/fisiología , Antiinflamatorios no Esteroideos/farmacología , Arterias/efectos de los fármacos , Biopsia , Índice de Masa Corporal , Peso Corporal/fisiología , Endotelio Vascular/fisiología , Femenino , Humanos , Inmunohistoquímica , Indometacina/farmacología , Miometrio/efectos de los fármacos , Óxido Nítrico/fisiología , Preeclampsia/fisiopatología , Embarazo , Transducción de Señal/efectos de los fármacos , Tromboxanos/fisiología , Vasoconstricción/fisiología , Vasodilatación/fisiologíaRESUMEN
The eNOS-/- mouse provides a well-characterized model of fetal growth restriction (FGR) with altered uterine and umbilical artery function and reduced utero- and feto-placental blood flow. Pomegranate juice (PJ), which is rich in antioxidants and bioactive polyphenols, has been posited as a beneficial dietary supplement to promote cardiovascular health. We hypothesized that maternal supplementation with PJ will improve uterine and umbilical artery function and thereby enhance fetal growth in the eNOS-/- mouse model of FGR. Wild type (WT, C57Bl/6J) and eNOS-/- mice were supplemented from E12.5-18.5 with either PJ in their drinking water or water alone. At E18.5 uterine (UtA) and umbilical (UmbA) arteries were isolated for study of vascular function, fetuses and placentas were weighed and fetal biometric measurements taken. PJ supplementation significantly increased UtA basal tone (both genotypes) and enhanced phenylephrine-induced contraction in eNOS-/- but not WT mice. Conversely PJ significantly reduced UtA relaxation in response to both acetylcholine (Ach) and sodium nitroprusside (SNP), endothelium dependent and independent vasodilators respectively from WT but not eNOS-/- mice. UmbA sensitivity to U46619-mediated contraction was increased by PJ supplementation in WT mice; PJ enhanced contraction and relaxation of UmbA to Ach and SNP respectively in both genotypes. Contrary to our hypothesis, the changes in artery function induced by PJ were not associated with an increase in fetal weight. However, PJ supplementation reduced litter size and fetal abdominal and head circumference in both genotypes. Collectively the data do not support maternal PJ supplementation as a safe or effective treatment for FGR.
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The ANP knockout mouse is reported to exhibit pregnancy-associated hypertension, proteinuria and impaired placental trophoblast invasion and spiral artery remodeling, key features of pre-eclampsia (PE). We hypothesized that these mice may provide a relevant model of human PE with associated fetal growth restriction (FGR). Here, we investigated pregnancies of ANP wild type (ANP(+/+)), heterozygous (ANP(+/-)) and knockout (ANP(-/-)) mice. Maternal blood pressure did not differ between genotypes (E12.5, E17.5), and fetal weight (E18.5) was unaffected. Placental weight was greater in ANP(-/-) versus ANP(+/+) mice. Therefore, in our hands, the ANP model does not express phenotypic features of PE with FGR.
Asunto(s)
Factor Natriurético Atrial/genética , Presión Sanguínea/genética , Retardo del Crecimiento Fetal/genética , Placenta/fisiopatología , Preeclampsia/genética , Animales , Factor Natriurético Atrial/metabolismo , Modelos Animales de Enfermedad , Femenino , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/fisiopatología , Ratones , Ratones Noqueados , Placenta/metabolismo , Preeclampsia/metabolismo , Preeclampsia/fisiopatología , EmbarazoRESUMEN
BACKGROUND: Maternal obesity is a frequent obstetric risk factor, linked with short- and long-term consequences for mother and child, including foetal overgrowth, growth restriction and stillbirth. The mechanisms underlying these pathologies remain unknown but likely involve the placenta. AIMS: To study placental cell turnover in relation to maternal body mass index (BMI). METHODS: Term placental villous tissue was randomly sampled from 24 pregnancies, with a range of maternal BMI of 19.5-49.6. Immunohistochemistry was performed for human chorionic gonadotropin, Ki67 and M30 and image analysis used to calculate syncytiotrophoblast area and proliferative and apoptotic indices. Results were compared categorically between women of BMI 18.5-24.9 (normal), BMI 30.0-39.9 (obese classes 1 and 2) and BMI 40+ (obese class 3) and continuously against BMI; p < 0.05 by the Kruskal-Wallis test or linear regression was considered statistically significant. RESULTS: Increased maternal BMI was associated with categorical (normal versus obese class 3 and obese classes 1 and 2 versus obese class 3, both p < 0.05) and continuous (r(2) = 0.24, p = 0.016) reductions in the proliferative index and a continuous reduction (r(2) = 0.17, p = 0.047) in the apoptotic index. DISCUSSION: Maternal obesity is associated with a dose-dependent reduction in placental villous proliferation and apoptosis which may increase susceptibility to adverse pregnancy outcomes.