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1.
Am J Obstet Gynecol ; 213(6): 853.e1-9, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26476107

RESUMEN

OBJECTIVE: The long-term maternal cardiovascular and metabolic implications associated with preeclampsia (PE) include risk of hypertension, heart disease, and metabolic syndrome. The objective of this study was to investigate if a recent history of PE was associated with detectable alterations in the circulating maternal proteome. STUDY DESIGN: Six-month postpartum plasma from women with a history of PE (n = 12) and women with uncomplicated obstetrical history (n = 12) were used for analysis. Depleted maternal plasma was analyzed by label-free liquid chromatography-mass spectrometry assay. Identified peptides were searched against the International Protein Index human database version 3.87. Exponentially modified protein abundance indices were used for comparison. Results were analyzed using pathway analysis software. RESULTS: A total of 126 eligible peptides were identified for analysis; 3 peptides were differentially expressed in the PE proteome, and an additional 5 peptides were unique to control subjects and 7 to PE subjects. PE peptide profiles were more strongly associated with markers of coagulation and complement activation compared to controls and mapped more significantly to cardiovascular disease (CVD) functions. Stratification of subjects by low (<39%) and high (≥39%) lifetime risk of CVD rather than by diagnosis produced similar findings. Comparison of controls (n = 6) to PE subjects (n = 6) without traditional cardiovascular risk factors found that while similar for body mass indices, blood pressure, and fasting lipid profiles at 6 months postpartum, PE peptide profiles continued to display stronger associations for coagulation and CVD functions. Global network analysis found that unique peptides to low-risk PE subjects were associated with cardiac infarction, CVD, and organismal injury and abnormalities. CONCLUSION: Markers of CVD risk and progression are evident in the maternal circulating proteome 6 months postpartum after PE. Augmentations in circulating peptide profiles occur in patients with previous PE who otherwise do not have clinically measurable cardiovascular risk factors. Our data highlight the need for the implementation of postpartum prevention programs in the PE population and identifies molecules that may be targeted for screening or therapeutic benefit.


Asunto(s)
Periodo Posparto/sangre , Preeclampsia/sangre , Proteoma/análisis , Proteínas 14-3-3/sangre , Adulto , Proteínas Sanguíneas/análisis , Enfermedades Cardiovasculares/sangre , Estudios de Casos y Controles , Caspasa 12/sangre , Proteínas del Citoesqueleto/sangre , Femenino , Humanos , Embarazo , Medición de Riesgo
2.
Am J Obstet Gynecol ; 210(5): 466.e1-5, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24334207

RESUMEN

OBJECTIVE: Fetal alcohol syndrome (FAS) is the most common cause of nongenetic mental retardation. Oxidative stress is one of the purported mechanisms. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is an enzyme involved in the production of reactive oxygen species. Our objective was to evaluate NOX in the fetal brain of a well-validated mouse model of FAS. STUDY DESIGN: Timed, pregnant C57BL/6J mice were injected intraperitoneally with 0.03 mL/g of either 25% ethyl alcohol or saline. Fetal brain, liver, and placenta were harvested on gestational day 18. The unit of analysis was the litter; tissue from 6-8 litters in the alcohol and control group was isolated. Evaluation of messenger ribonucleic acid (mRNA) expression of NOX subunits (DUOX1, DUOX2, NOX1, NOX2, NOX3, NOX4, NOXA1, NOXO1, RAC1, p22phox, and p67phox) was performed using quantitative real-time polymerase chain reaction; alcohol vs placebo groups were compared using a Student t test or a Mann-Whitney test (P < .05). RESULTS: Alcohol exposed fetal brains showed significant up-regulation in subunits DUOX2 (1.61 ± 0.28 vs 0.84 ± 0.09; P = .03), NOXA1 (1.75 ± 0.27 vs 1.09 ± 0.06; P = .04), and NOXO1 (1.59 ± 0.10 vs 1.28 ± 0.05; P = .02). Differences in mRNA expression in the placenta were not significant; p67phox was significantly up-regulated in alcohol-exposed livers. CONCLUSION: Various NOX subunits are up-regulated in fetal brains exposed to alcohol. This effect was not observed in the fetal liver or placenta. Given the available evidence, the NOX system may be involved in the causation of FAS through the generation of reactive oxygen species and may be a potential target for preventative treatment in FAS.


Asunto(s)
Trastornos del Espectro Alcohólico Fetal/enzimología , NADPH Oxidasas/fisiología , Animales , Encéfalo/embriología , Encéfalo/enzimología , Modelos Animales de Enfermedad , Femenino , Trastornos del Espectro Alcohólico Fetal/fisiopatología , Feto/enzimología , Ratones Endogámicos C57BL , NADP , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba/fisiología
3.
Am J Obstet Gynecol ; 211(4): 424.e1-7, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24905416

RESUMEN

OBJECTIVE: Lactation is associated with reduction in maternal metabolic disease and hypertension later in life; however, findings in humans may be confounded by socioeconomic factors. We sought to determine the independent contribution of lactation on cardiovascular parameters and adiposity in a murine model. STUDY DESIGN: Following delivery, CD-1 female mice were randomly divided into 2 groups: lactated (L; nursed pups for 3 weeks, n = 10), and nonlactated (NL; pups were removed after birth, n = 12). Blood pressure (BP) was assessed prepregnancy and at 1 and 2 months' postpartum. Visceral and subcutaneous adipose tissue determined by computed tomography and left ventricular ejection fraction, cardiac output, and the E/A ratio determined by microultrasound were evaluated at 1 and 2 months' postpartum. The results were analyzed using a Student t test (significance at P < .05). RESULTS: We observed a significantly different maternal BP at 2 months' postpartum with relatively greater BP in NL (systolic BP: NL, 122.2 ± 7.2 vs L, 96.8 ± 9.8 mm Hg; P = .04; diastolic BP: NL, 87.0 ± 6.8 vs L, 65.9 ± 6.2 mm Hg; P = .04). Visceral adipose tissue was significantly increased in NL mice at 1 (22.0 ± 4.1% vs 10.7 ± 1.8%, P = .04) and 2 months' postpartum (22.9 ± 3.5% vs 11.2 ± 2.2%, P = .02), whereas subcutaneous adipose tissue did not differ between the groups. At 2 months' postpartum, ejection fraction (51.8 ± 1.5% vs 60.5 ± 3.8%; P = .04), cardiac output (14.2 ± 1.0 vs 18.0 ± 1.3 mL/min; P = .02) and mitral valve E/A ratio (1.38 ± 0.06 vs 1.82 ± 0.13; P = .04) were significantly lower in NL mice than L mice. CONCLUSION: Our data provide evidence that interruption of lactation adversely affects postpartum maternal cardiovascular function and adiposity.


Asunto(s)
Adiposidad/fisiología , Lactancia/fisiología , Función Ventricular Izquierda/fisiología , Tejido Adiposo Blanco/fisiología , Animales , Presión Sanguínea/fisiología , Gasto Cardíaco/fisiología , Femenino , Ratones , Distribución Aleatoria , Volumen Sistólico/fisiología
4.
Am J Obstet Gynecol ; 208(5): 388.e1-388.e10, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23497796

RESUMEN

OBJECTIVE: Preeclampsia is associated with long-term adverse maternal health, such as cardiovascular and metabolic diseases. The objective of this study was to determine whether preeclampsia in a well-characterized animal model that was induced by overexpression of soluble fms-like tyrosine kinase-1 (sFlt1) results in alterations in the maternal circulating proteome that persist long after delivery. STUDY DESIGN: CD-1 mice at day 8 of gestation were injected with adenovirus that carried sFlt1 or the murine immunoglobulin G2α Fc fragment as control. Depleted maternal plasma was analyzed 6 months after delivery by label-free liquid chromatography-mass spectrometry assay. The tandem mass spectrometry data were searched against a mouse database, and the resultant intensity data were used to compare abundance of proteins across disease/control plasma pool. Results were analyzed with ingenuity pathways analysis. Right-tailed Fisher exact test was used to calculate a probability value. RESULTS: Of 150 proteins that are common for both groups, ingenuity pathways analysis determined 105 proteins that were ready for analysis. Diseases and disorders analysis showed significant enrichment of proteins that are associated with cardiovascular disease. Within this cluster, the most abundant proteins were associated with vascular disease, atherosclerosis, and atherosclerotic lesions. Other top disease clusters were inflammatory response, organismal injury and abnormalities, and hematologic and metabolic disease. CONCLUSION: Exposure to sFlt1-induced preeclampsia alters multiple biologic functions in mothers that persist later in life. Our results suggest that some of the long-term adverse outcomes that are associated with preeclampsia actually may be a consequence rather than a mere unmasking of an underlying predisposition. If similar results are found in humans, the development of preventive strategies for preeclampsia should also improve long-term maternal health.


Asunto(s)
Biomarcadores/sangre , Enfermedades Cardiovasculares/etiología , Preeclampsia/sangre , Proteoma/metabolismo , Animales , Enfermedades Cardiovasculares/sangre , Cromatografía Liquida , Modelos Animales de Enfermedad , Femenino , Espectrometría de Masas , Ratones , Preeclampsia/etiología , Embarazo , Distribución Aleatoria , Receptor 1 de Factores de Crecimiento Endotelial Vascular
5.
Am J Obstet Gynecol ; 208(4): 308.e1-7, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23313309

RESUMEN

OBJECTIVE: Pioglitazone (PIO), an antidiabetic drug of the thiazolidinedione family, improves glucose and lipid metabolism in muscle, adipose, and liver tissues via peroxisome proliferator-activated receptor gamma activation. We hypothesize that PIO therapy will improve the metabolic status of offspring exposed to maternal obesity in a mouse model developmentally programmed for metabolic syndrome. STUDY DESIGN: CD-1 female mice were fed a high-fat diet for 3 months prior to breeding and throughout pregnancy and lactation. The pups were weaned to a standard-fat diet. Offspring were randomly assigned to receive 40 mg/kg of PIO in 0.5% of methyl cellulose or 0.5% methyl cellulose by daily oral gavage for 2 weeks. The pre- and posttreatment total body weights of the pups were recorded. Visceral and subcutaneous adipose tissue were evaluated using microcomputed tomography. Serum analytes were measured. After treatment, minimally invasive microendoscopic fluorescence confocal imaging and intraperitoneal glucose tolerance tests were performed. The data were analyzed using appropriate statistical tests (significance, P < .05). RESULTS: PIO therapy resulted in lower total body weight and lower visceral adipose tissue gain and increased subcutaneous adipose tissue. PIO significantly lowered triglycerides, insulin levels, and homeostasis model assessment of insulin resistance in males and fasting glucose in females. There was a trend toward larger adipocyte size. CONCLUSION: Short-term PIO therapy in the offspring of obese mothers attenuates metabolic changes associated with the developmental programming of metabolic syndrome. These novel data suggest a potential role for drugs that activate peroxisome proliferator-activated receptor gamma receptors to prevent metabolic syndrome in the adult offspring at risk to develop metabolic alterations.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Hipoglucemiantes/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Obesidad/complicaciones , Tiazolidinedionas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Síndrome Metabólico/etiología , Ratones , PPAR gamma , Pioglitazona , Embarazo
6.
Am J Obstet Gynecol ; 206(4): 358.e19-22, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22365038

RESUMEN

OBJECTIVE: Superoxide dismutase, glutathione peroxidase, and catalase prevent cellular damage produced by free radicals. Our objective was to evaluate if prenatal alcohol exposure decreased the expression of antioxidant enzymes in the brain, liver, or placenta of fetal mice. STUDY DESIGN: Timed, pregnant C57BL6/J mice were treated on gestational day 8 with intraperitoneal injection of alcohol (0.03 mL/g) or saline (control). Fetuses were harvested on gestational day 18. Fetal brain, liver, and placenta were analyzed for mRNA expression of superoxide dismutase, glutathione peroxidase, and catalase by real-time polymerase chain reaction, with 18S RNA used as reference. RESULTS: Superoxide dismutase, glutathione peroxidase, and catalase expression was lower in fetal brains exposed to alcohol with no differences detected in the liver or placenta between the 2 groups. CONCLUSION: Maternal alcohol consumption causes a decrease in superoxide dismutase, glutathione peroxidase, and catalase expression in the fetal brain. This may explain the long-term neurologic findings in fetal alcohol syndrome.


Asunto(s)
Catalasa/biosíntesis , Trastornos del Espectro Alcohólico Fetal/enzimología , Glutatión Peroxidasa/biosíntesis , Superóxido Dismutasa/biosíntesis , Animales , Antioxidantes/metabolismo , Encéfalo/enzimología , Modelos Animales de Enfermedad , Femenino , Hígado/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Placenta/enzimología , Embarazo
7.
Am J Perinatol ; 29(8): 615-22, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22639355

RESUMEN

OBJECTIVE: To estimate the effects of prostaglandin E1 (PGE1) and E2 (PGE2) on myometrial contractility and structure in vitro. STUDY DESIGN: Myometrial strips from 18 women were incubated with PGE1 (10-5 mol/L), PGE2 (10-5 mol/L), or solvent (CTR) for up to 360 minutes in organ chambers for isometric tension recording. The area under the contraction curve, total collagen content, and percentage of the area covered by connective tissue were calculated at various time periods. RESULTS: PGE1 significantly increased in vitro myometrial contractility up to 90 minutes when compared with PGE2 and CTR (p < 0.01) and up to 180 minutes as compared with PGE2 (p < 0.05). After 360 minutes, CTR and PGE1 samples had lower total collagen content and area covered by connective tissue than PGE2 (p < 0.01). CONCLUSION: The effects of prostaglandins on the uterus cannot be solely explained by contractility. Treatment with PGE1 significantly increased myometrial contractions and decreased both total collagen content and the area covered by connective tissue. Such findings may explain the higher rates of vaginal delivery, tachysystole, and uterine rupture associated with PGE1 use.


Asunto(s)
Alprostadil/farmacología , Dinoprostona/farmacología , Contracción Uterina/efectos de los fármacos , Útero/anatomía & histología , Adulto , Colágeno/química , Tejido Conectivo/anatomía & histología , Femenino , Humanos , Miometrio/química , Técnicas de Cultivo de Órganos , Contracción Uterina/fisiología
8.
Am J Perinatol ; 29(9): 699-704, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22644831

RESUMEN

OBJECTIVE: To investigate the effects of different pharmacological induction agents on myometrial contractility. STUDY DESIGN: Myometrial biopsies were obtained from 13 term nonlaboring women undergoing scheduled cesarean delivery. Tissue strips were suspended in organ chambers for isometric tension recording. The effects of cumulative doses (10-10 mol/L to 10-5 mol/L) of prostaglandin E1 (PGE1), E2 (PGE2), and oxytocin on spontaneous uterine contractility were determined. Areas under the contraction curve were compared using one-way analysis of variance on ranks with Dunn post hoc test. RESULTS: Oxytocin-induced myometrial contractility was superior to PGE1, PGE2, and time controls (CTR) at all the concentrations tested. When only prostaglandins were compared with CTR, PGE1 10-5 mol/L increased myometrial contractility, and PGE2 had no effects. CONCLUSION: Oxytocin and prostaglandins have different effects on myometrial contractility accounting for different mechanisms of action and side effects. The increased uterine contractility observed with PGE1 as compared with PGE2 can contribute to explain the higher success of vaginal delivery.


Asunto(s)
Alprostadil/farmacología , Dinoprostona/farmacología , Contracción Isométrica/efectos de los fármacos , Miometrio/patología , Oxitócicos/farmacología , Oxitocina/farmacología , Adulto , Análisis de Varianza , Biopsia , Femenino , Humanos , Técnicas In Vitro , Trabajo de Parto Inducido/métodos , Embarazo
9.
Am J Physiol Heart Circ Physiol ; 301(5): H1781-7, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21890691

RESUMEN

This study examines the effects of VEGF-121 therapy in an animal model of preeclampsia induced by overexpression of soluble VEGF receptor 1 (sVEGFR-1). At day 8 of gestation, CD-1 mice were implanted with subcutaneous osmotic pumps containing either VEGF-121 or vehicle and fitted with telemetric blood pressure (BP) catheters for continuous BP monitoring (days 8-18 of gestation). On day 9, the animals in the VEGF-121 group were randomly allocated for injection with adenovirus carrying sVEGFR-1 or the murine immunoglobulin G2α Fc fragment (mFc) as virus control (Adv-sVEGFR-1; Adv-mFc). Animals in the vehicle group were injected with Adv-sVEGFR-1. On day 18, mice were euthanized, placentas and pups weighted, carotid arteries isolated, and their responses studied in vitro using a wire myograph for isometric tension recording. In mice overexpressing sVEGFR-1, treatment with VEGF-121 significantly reduced BP from days 10 to 18 of gestation compared with that of vehicle. VEGF-sVEGFR-1 animals had significantly higher vasorelaxant response to sodium nitroprusside and significantly lower contractile response to the thromboxane agonist (U-46619) compared with that of the vehicle-sVEGFR-1 mice. Phenylephrine and acetylcholine responses did not significantly vary between the VEGF-sVEGFR-1 and the vehicle-sVEGFR-1 mice. Average pup weight was significantly lower in the vehicle-sVEGFR-1 group compared with the VEGF-sVEGFR-1 and VEGF-mFc groups. In conclusion, VEGF-121 therapy attenuates vascular dysfunction and diminishes intrauterine growth abnormality in an animal model of preeclampsia induced by overexpression of sVEGFR-1. Modulation of VEGF pathway turns into a promising therapeutic approach of preeclampsia.


Asunto(s)
Antihipertensivos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Preeclampsia/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Receptor 1 de Factores de Crecimiento Endotelial Vascular/agonistas , Adenoviridae/genética , Animales , Monitoreo Ambulatorio de la Presión Arterial , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/prevención & control , Peso Fetal , Vectores Genéticos , Edad Gestacional , Bombas de Infusión Implantables , Infusiones Subcutáneas , Ratones , Preeclampsia/genética , Preeclampsia/metabolismo , Preeclampsia/fisiopatología , Embarazo , Proteínas Recombinantes/administración & dosificación , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología
10.
Am J Obstet Gynecol ; 205(4): 366.e1-5, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22083058

RESUMEN

OBJECTIVE: We sought to investigate the mechanisms of action by which pravastatin improves vascular reactivity in a mouse model of preeclampsia induced by overexpression of soluble Fms-like tyrosine kinase-1 (sFlt)-1. STUDY DESIGN: Pregnant CD-1 mice were randomly allocated to tail vein injection with adenovirus carrying sFlt-1 or murine immunoglobulin G2 Fc (control), and thereafter to receive pravastatin (5 mg/kg/d) or water. Mice were sacrificed at gestational day 18. Protein expression of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor receptor-1, and hemeoxygenase-1 were assayed by Western blot in aorta, liver, and kidneys. Serum total cholesterol concentrations were measured. RESULTS: Pravastatin up-regulated eNOS expression in the aorta of sFlt-1 mice by nearly 2-fold (P = .005) to levels similar to control mice. Total cholesterol levels, vascular endothelial growth factor receptor-1, and hemeoxygenase-1 protein expression were similar across groups. CONCLUSION: Pravastatin prevents vascular dysfunction in part by up-regulation of eNOS in the vasculature. Our data support a role for statins in preeclampsia prevention.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pravastatina/uso terapéutico , Preeclampsia/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Preeclampsia/etiología , Embarazo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/fisiología
11.
Am J Obstet Gynecol ; 204(5): 398.e1-8, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21444063

RESUMEN

OBJECTIVE: We sought to establish a model of fetal programming of metabolic syndrome by exposure to soluble fms-like tyrosine kinase-1 (sFlt1)-induced preeclampsia (PE) and preexisting maternal obesity (MO). STUDY DESIGN: CD-1 female mice were placed on either standard or high-fat diet for 3 months. On day 8 of pregnancy, mice were injected with either adenovirus-carrying sFlt1 or adenovirus-carrying murine immunoglobulin G2α Fc fragment. Offspring were studied at 6 months of age. RESULTS: Exposure to MO with/without PE resulted in significant increase in progeny's weight and adiposity. Blood pressure in males was significantly increased due to MO with PE. Metabolic blood analytes were affected in males and females exposed to only PE or MO with/without PE; inflammatory-in females exposed to MO with/without PE and males born to MO with PE; atherosclerotic-in females exposed to MO. CONCLUSION: Exposure to maternal prepregnancy obesity and sFlt1-induced preeclampsia alter the offspring's blood pressure, metabolic, inflammatory, and atherosclerotic profiles later in life.


Asunto(s)
Desarrollo Fetal/fisiología , Síndrome Metabólico/metabolismo , Obesidad/metabolismo , Preeclampsia/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/farmacología , Adiposidad , Animales , Presión Sanguínea , Femenino , Masculino , Síndrome Metabólico/etiología , Ratones , Preeclampsia/inducido químicamente , Embarazo
12.
Am J Physiol Heart Circ Physiol ; 298(1): H189-93, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19915174

RESUMEN

Our aim was to evaluate the long-term effects of preeclampsia on vascular function in a mouse model induced by sFlt-1 overexpression. CD-1 mice at day 8 of gestation were injected via the tail vein with adenovirus carrying sFlt1 (AdsFlt1), adenovirus carrying the murine IgG2alpha Fc fragment as the adenovirus control (AdmFc), or saline. Vascular function in the mothers was investigated 6-8 mo after delivery by recording blood pressure (BP) by telemetry (AdsFlt1 n = 8, AdmFc n = 6, saline n = 4) and exploring carotid artery reactivity in a wire myograph (AdsFlt1 n = 6, AdmFc n = 8, saline n = 4). sFlt-1 blood levels at 6-8 mo postpartum had returned to low levels and were comparable between the three groups (P = 0.808). There was no statistically significant difference in BP (P = 0.067) or vascular reactivity between the three groups of postpartum mice (phenylephrine P = 0.079, thromboxane P = 0.979, serotonin P = 0.659, acetylcholine P = 0.795, sodium nitroprusside P = 0.728, isoproterenol P = 0.370). Our results indicate that in a mouse model overexpression of sFlt-1 does not lead to increased in BP and altered vascular function in the absence of the pregnancy and has no long-term effect on BP and vascular function in the postpartum mothers. Our findings favor the hypothesis that increased cardiovascular diseases in women with history of preeclampsia are likely the result of preexisting risk factors common to preeclampsia and cardiovascular diseases.


Asunto(s)
Hemodinámica/fisiología , Preeclampsia/fisiopatología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Adenoviridae/fisiología , Animales , Animales Recién Nacidos , Presión Sanguínea/efectos de los fármacos , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Técnicas de Transferencia de Gen , Hemodinámica/efectos de los fármacos , Ratones , Periodo Posparto/fisiología , Preeclampsia/genética , Embarazo , Telemetría , Vasoconstrictores/farmacología , Vasodilatadores/farmacología
13.
Am J Obstet Gynecol ; 203(6): 596.e1-5, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20965489

RESUMEN

OBJECTIVE: To investigate the effect of intracervical hyaluronidase on the biomechanical properties of the cervix and on uterine contractility. STUDY DESIGN: Sprague-Dawley rats (n = 33, term day 22) were injected with hyaluronidase (100 IU) or saline solution on day 18 of gestation (n = 8-9/group). On day 21, labor was induced with mifepristone (8 mg/rat). Injection-to-delivery times were recorded. Biomechanical properties of the cervix were assessed using stretch-tension analysis. Myometrial contractility was investigated in response to hyaluronidase (0.2-200 IU/mL), oxytocin (10(-10)M to 10(-5)M), and potassium chloride (60 mM). RESULTS: Delivery times were shorter in the hyaluronidase group (P = .03). Cervices of the treated animals showed higher measures of elasticity and plasticity (P = .02 for both). Myometrial sensitivity to hyaluronidase, oxytocin, or potassium chloride was not affected by the cervical application of hyaluronidase (P > .05 for all). CONCLUSION: Cervical hyaluronidase treatment shortens labor and alters the biomechanical properties of the cervix, independent of the myometrium.


Asunto(s)
Cuello del Útero/efectos de los fármacos , Hialuronoglucosaminidasa/farmacología , Trabajo de Parto/efectos de los fármacos , Contracción Uterina/efectos de los fármacos , Animales , Fenómenos Biomecánicos , Maduración Cervical/efectos de los fármacos , Cuello del Útero/fisiología , Modelos Animales de Enfermedad , Femenino , Trabajo de Parto/fisiología , Miometrio/efectos de los fármacos , Miometrio/fisiología , Embarazo , Preñez , Distribución Aleatoria , Ratas , Factores de Tiempo , Contracción Uterina/fisiología
14.
Am J Obstet Gynecol ; 203(3): 252.e1-5, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20541728

RESUMEN

OBJECTIVE: We sought to test the hypothesis that sildenafil citrate (SC) at low concentrations potentiates the tocolytic effects of nifedipine in vitro. STUDY DESIGN: Myometrial biopsies were obtained from 22 term nonlaboring women undergoing scheduled cesarean delivery. Tissue strips were suspended in organ chambers for isometric tension recording, and incubated for 30 minutes with either SC at 231 ng/mL or solvent. The effects of cumulative doses (10(-10) to 10(-5) mol/L) of nifedipine on spontaneous and oxytocin-induced uterine contractility were then determined. Areas under the contraction curve were compared using 1-way analysis of variance with Tukey post hoc test (significance: P < .05). RESULTS: Nifedipine significantly inhibited spontaneous and oxytocin-induced myometrial contractility. Preincubation with SC increased response to nifedipine and significantly potentiated its inhibitory effect at 10(-8) mol/L, without affecting oxytocin-induced contractile response. CONCLUSION: At concentrations within a therapeutic window, SC increases myometrial sensitivity to nifedipine.


Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Nifedipino/farmacología , Piperazinas/farmacología , Sulfonas/farmacología , Contracción Uterina/efectos de los fármacos , Vasodilatadores/farmacología , Adulto , Biopsia , Femenino , Humanos , Técnicas In Vitro , Miometrio/efectos de los fármacos , Miometrio/patología , Oxitócicos/farmacología , Oxitocina/farmacología , Embarazo , Purinas/farmacología , Citrato de Sildenafil
15.
Am J Obstet Gynecol ; 203(3): 261.e1-5, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20633871

RESUMEN

OBJECTIVE: We sought to investigate the effect of body mass index (BMI) on in vitro response to tocolytics. STUDY DESIGN: Myometrial biopsies were obtained at the time of scheduled cesarean deliveries from term nonlaboring women with BMI < or =29.9 (26.3 +/- 1.3; n = 7), 30-34.9 (31.8 +/- 1.2; n = 16), and > or = 35 (39.5 +/- 4.9; n = 9). Tissue strips were suspended in organ chambers for isometric tension recording. The effects of cumulative doses (10(-10) to 10(-5) mol/L) of nifedipine or indomethacin on spontaneous uterine contractility were determined. Areas under the contraction curve were compared using 1-way analysis of variance with Tukey post hoc test. RESULTS: Myometrial response to tocolytics did not differ between the BMI groups. Nifedipine, but not indomethacin, significantly inhibited myometrial contractility independent of BMI. CONCLUSION: BMI does not affect uterine response to tocolytics in isolated uterine tissue from term nonlaboring women.


Asunto(s)
Índice de Masa Corporal , Indometacina/farmacología , Nifedipino/farmacología , Tocolíticos/farmacología , Contracción Uterina/efectos de los fármacos , Adulto , Área Bajo la Curva , Biopsia , Femenino , Humanos , Técnicas In Vitro , Miometrio/efectos de los fármacos , Miometrio/patología , Embarazo
16.
Curr Allergy Asthma Rep ; 10(6): 453-9, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20617403

RESUMEN

Asthma is a common disease, and the number of people diagnosed with it increases every year. Although genetic background and environmental exposures play major roles in the development of asthma, one cannot overlook the developmental origin of adult disease or fetal programming theory. This review examines the social, genetic, and environmental factors that are associated with fetal programming of asthma. We also present recent studies from our laboratory that strengthen these observations. It is our hope that the reader will come away with a current view of fetal programming in asthma.


Asunto(s)
Asma/inmunología , Desarrollo Fetal/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Adulto , Asma/etiología , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Masculino , Embarazo , Factores de Riesgo
17.
Am J Obstet Gynecol ; 200(4): 432.e1-7, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19318153

RESUMEN

OBJECTIVE: The purpose of this study was to test the hypothesis that prepregnancy obesity and soluble fms-like tyrosine kinase-1 (sFlt-1)-induced preeclampsia lead to altered vascular function in the offspring later in life. STUDY DESIGN: CD-1 female mice were placed on a low-fat (LF) or high-fat (HF) diet before mating. On day 8 of pregnancy, the HF mice were injected with adenovirus that carried either sFlt-1 (HF sFlt-1) or murine immunoglobulin G2alpha Fc fragment (HF mFc). LF dams received saline solution. After being weaned, all offspring were placed on a standard diet. At 3 months of age, the carotid artery was isolated for in vitro vascular reactivity studies. RESULTS: Among male offspring, the response to phenylephrine was significantly lower in the HF sFlt-1 group. The response to serotonin in males and to thromboxane in females was lower in the HF sFlt-1 and HF mFc groups. In females, the HF sFlt-1 and LF groups displayed less relaxation to acetylcholine. The response to phenylephrine was significantly lower in females than males in the HF mFc and LF groups. The response to thromboxane was significantly lower in the HF sFlt-1 females, compared with males. CONCLUSION: Prepregnancy obesity and preeclampsia alter fetal programming of adult vascular function. The mechanism is complex and gender specific.


Asunto(s)
Vasos Sanguíneos/fisiología , Desarrollo Fetal , Obesidad , Preeclampsia , Factores de Edad , Animales , Femenino , Masculino , Ratones , Obesidad/complicaciones , Preeclampsia/etiología , Embarazo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/administración & dosificación
18.
Int Arch Allergy Immunol ; 147(2): 140-6, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18520159

RESUMEN

BACKGROUND: We have previously shown that in sensitized guinea pigs premature labor can be induced by a type I hypersensitivity reaction. We further hypothesize that premature labor occurs due to increased uterine contractility caused by activation of mast cells and possibly eosinophils, and collective release of their mediators. The objective of this study was to test the hypothesis that IgE-independent mast cell degranulation could increase uterine contractility. METHODS: Longitudinal uterine strips from nonpregnant and pregnant guinea pigs were incubated in organ chambers with vehicle, histamine H(1), serotonin 5-HT(2)/5-HT(1C), thromboxane A(2), leukotriene D(4) receptor antagonists, mast cell stabilizer, and cyclooxygenase or lipoxygenase inhibitors. Then, supernatant, obtained after activation of a mast cell line (MC/9) with compound 48/80, culture medium, or compound 48/80 alone were added. Cumulative concentration-response curves to histamine and serotonin were also obtained. RESULTS: The supernatant and compound 48/80 significantly increased contractility of uterine strips. A mast cell stabilizer considerably reduced the effect of compound 48/80. Other substances attenuated uterine contractile responses to supernatant and compound 48/80, and responses varied depending on the pregnancy period. Histamine and serotonin increased contractility of uterine strips, and uterine sensitivity to these agents were dependent on gestational age. CONCLUSIONS: In summary, mast cells increase uterine contractility through multiple mediators, and uterine responses to these mediators are dependent on gestational age. We postulate that the simultaneous release of these mast cell/eosinophil mediators in the uterus could be a stimulus to trigger and/or maintain myometrial contractions during preterm and term labor.


Asunto(s)
Mastocitos/efectos de los fármacos , Miometrio/efectos de los fármacos , Embarazo/fisiología , p-Metoxi-N-metilfenetilamina/farmacología , Animales , Línea Celular , Femenino , Cobayas , Inmunoglobulina E/inmunología , Técnicas In Vitro , Mastocitos/inmunología , Ratones , Contracción Muscular/efectos de los fármacos , Miometrio/fisiología
19.
Am J Obstet Gynecol ; 199(2): 165.e1-5, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18359469

RESUMEN

OBJECTIVE: The objective of this study was to examine the role of maternal hypercholesterolemia in fetal programming of adult vascular function using transgenic mice lacking the low-density lipoprotein receptor (LDLR). STUDY DESIGN: Homozygous LDLR knockout mice (B6.129S7-Ldlr(tm1Her)/J, LDLR(-/-KO)) and their wild-type controls (C57BL/6J, LDLR(+/+WT)) were cross-bred to produce 4 litter groups: LDLR(-/-KO), maternally derived heterozygous (LDLR(+/-Mat)), paternally derived heterozygous (LDLR(+/-Pat)) and LDLR(+/+WT). Female and male offspring were killed at 10-12 weeks of age, and carotid arteries were used for in vitro experiments. RESULTS: The dose responses to phenylephrine were significantly higher in LDLR(-/-KO) and LDLR(+/-Mat) male offspring. The contractile responses to phenylephrine in female mice were significantly increased only in the LDLR(-/-KO) offspring. Maximal Ca(2+) contraction was higher in LDLR(-/-KO) male and female offspring. CONCLUSION: Despite being genomically similar, heterozygous offspring that developed in a hypercholesterolemic maternal environment had abnormal vascular responses later in life compared with those that developed in a normal environment.


Asunto(s)
Vasos Sanguíneos/embriología , Hipercolesterolemia/embriología , Complicaciones Cardiovasculares del Embarazo/fisiopatología , Receptores de LDL/fisiología , Animales , Arterias Carótidas/fisiología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Hipercolesterolemia/fisiopatología , Técnicas In Vitro , Ratones , Ratones Noqueados , Ratones Transgénicos , Fenilefrina/farmacología , Embarazo , Vasoconstrictores/farmacología
20.
Am J Obstet Gynecol ; 199(6): 658.e1-6, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18722575

RESUMEN

OBJECTIVE: The aims of this study were to investigate the effects of ovalbumin challenge on uterine and cervical contractility, intrauterine pressure, and uterine electromyography activity in sensitized guinea pigs. STUDY DESIGN: Guinea pigs were sensitized by injection of ovalbumin-aluminum hydroxide suspension. Control animals were injected with the aluminum hydroxide suspension only. On days 55-57 of pregnancy, longitudinal uterine and cervical strips from guinea pigs were prepared for isometric tension recording. Nonpregnant guinea pigs were outfitted with telemetric transducers to record intrauterine pressure and uterine electromyography. RESULTS: Ovalbumin significantly increased contractility of uterine and cervical strips from sensitized versus nonsensitized animals. These effects were abolished by histamine H(1) receptor antagonist in uterine strips and by histamine H(1) receptor antagonist and a mast cell stabilizer in cervical strips from sensitized animals. Cyclooxygenase and 5-lipoxygenase inhibitors had no significant effect on the response to ovalbumin. Treatment with ovalbumin in vivo significantly increased intrauterine pressure and uterine electromyography activity in sensitized but not in nonsensitized, animals. CONCLUSION: Our findings indicate that type I hypersensitivity reactions may be important in mediating uterine contractility in pregnant and nonpregnant states.


Asunto(s)
Cuello del Útero/inmunología , Miometrio/efectos de los fármacos , Ovalbúmina/farmacología , Preñez , Contracción Uterina/inmunología , Animales , Cuello del Útero/efectos de los fármacos , Electromiografía , Femenino , Cobayas , Hipersensibilidad Inmediata/inmunología , Inmunización , Inyecciones Intraperitoneales , Contracción Muscular/efectos de los fármacos , Contracción Muscular/inmunología , Miometrio/inmunología , Ovalbúmina/inmunología , Embarazo , Probabilidad , Distribución Aleatoria , Valores de Referencia , Sensibilidad y Especificidad , Contracción Uterina/efectos de los fármacos
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