RESUMO
Increasing placental perfusion (PP) could improve outcomes of growth-restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)-5 inhibitors, which induce vasodilatation of vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116-117 days' gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120-123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then â¼15-75 min (TAD 1) and â¼75-135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T2 oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion-Relaxation Combined Imaging for Detailed Placental Evaluation-'DECIDE' technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal-placental blood volume fraction was increased in the TAD 2 period. Fetal D O 2 ${D_{{{\mathrm{O}}_2}}}$ and V Ì O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal-placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA D O 2 ${D_{{{\mathrm{O}}_2}}}$ .
Assuntos
Oxigênio , Placenta , Circulação Placentária , Tadalafila , Artéria Uterina , Animais , Feminino , Tadalafila/farmacologia , Tadalafila/administração & dosagem , Gravidez , Ovinos , Artéria Uterina/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placenta/irrigação sanguínea , Circulação Placentária/efeitos dos fármacos , Oxigênio/sangue , Fluxo Sanguíneo Regional/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/administração & dosagem , Imageamento por Ressonância Magnética , Feto/irrigação sanguínea , Feto/efeitos dos fármacosRESUMO
Maternal inhalation exposure to engineered nanomaterials (ENM) has been associated with microvascular dysfunction and adverse cardiovascular responses. Pregnancy requires coordinated vascular adaptation and growth that are imperative for survival. Key events in pregnancy hallmark distinct periods of gestation such as implantation, spiral artery remodeling, placentation, and trophoblast invasion. Angiotensin II (Ang II) is a critical vasoactive mediator responsible for adaptations and is implicated in the pathology of preeclampsia. If perturbations occur during gestation, such as those caused by ENM inhalation exposure, then maternal-fetal health consequences may occur. Our study aimed to identify the period of gestation in which maternal microvascular functional and fetal health are most vulnerable. Additionally, we wanted to determine if Ang II sensitivity and receptor density is altered due to exposure. Dams were exposed to ENM aerosols (nano-titanium dioxide) during three gestational windows: early (EE, gestational day (GD) 2-6), mid (ME, GD 8-12) or late (LE, GD 15-19). Within the EE group dry pup mass decreased by 16.3% and uterine radial artery wall to lumen ratio (WLR) increased by 25.9%. Uterine radial artery response to Ang II sensitivity increased by 40.5% in the EE group. Ang II receptor density was altered in the EE and LE group with decreased levels of AT2R. We conclude that early gestational maternal inhalation exposures resulted in altered vascular anatomy and physiology. Exposure during this time-period results in altered vascular reactivity and changes to uterine radial artery WLR, leading to decreased perfusion to the fetus and resulting in lower pup mass.
Assuntos
Angiotensina II/farmacologia , Nanopartículas Metálicas/toxicidade , Microcirculação , Circulação Placentária , Titânio/toxicidade , Artéria Uterina/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Aerossóis , Animais , Estradiol/sangue , Feminino , Idade Gestacional , Exposição por Inalação , Exposição Materna , Nanopartículas Metálicas/administração & dosagem , Gravidez , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/agonistas , Receptor Tipo 1 de Angiotensina/metabolismo , Titânio/administração & dosagem , Artéria Uterina/fisiopatologiaRESUMO
[Figure: see text].
Assuntos
Células Endoteliais/metabolismo , Sulfeto de Hidrogênio/metabolismo , Fator de Transcrição Sp1/metabolismo , Artéria Uterina/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Fator de Transcrição YY1/metabolismo , Adulto , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Regiões Promotoras Genéticas , Fator de Transcrição Sp1/genética , Transcrição Gênica , Artéria Uterina/efeitos dos fármacos , Fator de Transcrição YY1/genéticaRESUMO
Cervical ectopic pregnancy (CEP) is one of the rarest types of ectopic pregnancy. Early detection of such cases increases the chances of conservative treatment and fertility preservation. Within 6 weeks of each other, 2 women were admitted to the OB/GYN Department with cervical ectopic pregnancies. They were successfully treated with a double dose of methotrexate and super-selective uterine artery branch embolization (SUABE). Taking into account health and economic considerations, for instance the optimal recovery time, and lower costs of operating theater time, laboratory testing and outpatient observation, it seems that safe, minimally invasive, fertility-saving, effective systemic administration of MTX in combination with SUABE, can be a rational alternative to cervical ectopic pregnancy treatment.
Assuntos
Colo do Útero/cirurgia , Metotrexato/administração & dosagem , Gravidez Ectópica/cirurgia , Artéria Uterina/cirurgia , Adulto , Colo do Útero/irrigação sanguínea , Feminino , Humanos , Gravidez , Gravidez Ectópica/tratamento farmacológico , Artéria Uterina/efeitos dos fármacos , Embolização da Artéria UterinaRESUMO
Bisphenol A (BPA) is a widespread environmental contaminant, found in human fluids and tissues. Maternal BPA exposure is associated with alterations in pregnancy outcomes. Because maternal uterine circulation plays a crucial role in normal placenta and fetal growth, we hypothesized that BPA compromises the function of uterine arteries (UAs) and fetoplacental development. Female rats were orally administered with BPA (2.5, 25 and 250 µg/kg/day) or with its vehicle (ethanol) for 30 days before pregnancy and during the first 20 days of pregnancy. To compare the effect of BPA in the reproductive vs. systemic circulation, it was tested on UAs and mesenteric arteries (MAs). Arteries were isolated and examined by pressure myography. Moreover, fetuses and placentas were weighed to provide an index of reproductive performance. In UAs of BPA-treated rats, lumen diameter, acetylcholine-relaxation and expressions of endothelial nitric oxide synthase 3 (NOS3), estrogen receptor α (ERα) and peroxisome proliferator-activated receptor É£ (PPARÉ£) were reduced. Conversely, no changes were observed in MAs. BPA treatment also reduced placental weights, while fetal weights were increased. For the first time, our results indicate that UAs represent a specific target of BPA during pregnancy and provide insight into the molecular mechanisms that underlie its negative effects on pregnancy outcomes.
Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Compostos Benzidrílicos/efeitos adversos , Desenvolvimento Fetal/efeitos dos fármacos , Exposição Materna/efeitos adversos , Fenóis/efeitos adversos , Placenta/efeitos dos fármacos , Artéria Uterina/efeitos dos fármacos , Animais , Biomarcadores , Relação Dose-Resposta a Droga , Feminino , Placenta/metabolismo , Gravidez , Ratos , Artéria Uterina/metabolismo , Artéria Uterina/patologiaRESUMO
Uterine artery endothelium undergoes a form of functional adaptation during pregnancy because of an increase in Cx43 communication, resulting in increased Ca2+/IP3 exchange and more synchronous and sustained vasodilator production. We have shown previously that acute exposure to growth factors and TNF can block this adaptation through ERK and/or Src-mediated Cx43 phosphorylation. In preeclampsia such adapted function is already missing, but while elevated TNF is associated with this condition, particularly after 28 weeks (late PE), elevated circulating VEGF165 is not. Given PE is a long term condition emerging in the second half of pregnancy, and is often associated with added edema, we now compare the chronic effects of these two factors on the cell monolayer in order to establish if the breakdown of junctional adherens and tight junctional assemblies in which Cx43 resides could also explain loss of vasodilatory function. We report that while TNF can degrade monolayer integrity even in the 0.1-1 ng/ml physiologic range, VEGF up to 10 ng/ml does not. In addition, the progressive action of TNF is mediated through Src and ERK signaling to promote internalization and destruction of VE-Cadherin (VE-Cad) and ZO-1, as well as the expression and secretion of a variety of proteases. At least one protein degraded from the extracellular space is VE-Cad, resulting in release of a shed VE-Cad protein product, and consistent with monolayer breakdown being sensitive to both Src and MEK/ERK kinase inhibitors and the general protease inhibitor GM6001. We conclude that the greater association of TNF with 'late' PE is as much due to its longer term destabilizing effects on junctional assemblies as it is to acute closure of Cx43 channels themselves. New therapies aimed at stabilizing these junctional assemblies may help treat this hypertensive condition.
Assuntos
Conexina 43/metabolismo , Pré-Eclâmpsia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Artéria Uterina/citologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Técnicas de Cultura de Células , Células Cultivadas , Meios de Cultura/química , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Gravidez , Fator de Necrose Tumoral alfa/farmacologia , Artéria Uterina/efeitos dos fármacos , Artéria Uterina/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Proteína da Zônula de Oclusão-1/metabolismo , Quinases da Família src/metabolismoRESUMO
INTRODUCTION: Adenomyosis associated abnormal uterine bleeding (AUB-A) often remains non-responsive to medical management. Uterine sparing treatment in young patients presenting with refractory AUB-A poses a challenge. CASE REPORT: A 28-years-old woman presenting with AUB-A with failed medical therapy did not improve with uterine artery embolization (UAE). She underwent a second session of UAE with smaller embolic particles to which she responded. The reported case is interesting as patient conceived spontaneously despite transiently diminished post-UAE ovarian reserves, indicating spontaneous recovery of ovarian function. CONCLUSION: UAE is a promising option for young patients, though UAE for adenomyosis may require smaller embolic particles to be effective which may diminish ovarian reserves due to non-target effects, however recovery is possible in young patients..
Assuntos
Adenomiose/complicações , Embolização da Artéria Uterina/métodos , Artéria Uterina/efeitos dos fármacos , Adenomiose/terapia , Adulto , Feminino , Humanos , Gravidez , Resultado da Gravidez/epidemiologia , Resultado do TratamentoRESUMO
Preeclampsia (PE) is characterized by new-onset hypertension in association with elevated natural killer (NK) cells and inflammatory cytokines, which are likely culprits for decreased fetal weight during PE pregnancies. As progesterone increases during normal pregnancy, it stimulates progesterone-induced blocking factor (PIBF). PIBF has been shown to decrease inflammation and cytolytic NK cells, both of which are increased during PE. We hypothesized that PIBF reduces inflammation as a mechanism to improve hypertension in the preclinical reduced uterine perfusion pressure (RUPP) rat model of PE. PIBF (2.0 µg/mL) was administered intraperitoneally on gestational day 15 to either RUPP or normal pregnant (NP) rats. On day 18, carotid catheters were inserted. Mean arterial blood pressure (MAP) and samples were collected on day 19. MAP in NP rats (n = 11) was 100 ± 2 mmHg and 105 ± 3 mmHg in NP + PIBF rats (n = 8) and 122 ± 1 mmHg in RUPP rats (n = 10), which improved to 110 ± 2 mmHg in RUPP + PIBF rats (n = 11), P < 0.05. Pup weight was 2.4 ± 0.1 g in NP, 2.5 ± 0.1 g in NP + PIBF, 1.9 ± 0.1 g in RUPP, and improved to 2.1 ± 0.1 g in RUPP + PIBF rats. Circulating and placental cytolytic NK cells, IL-17, and IL-6 were significantly reduced while IL-4 and T helper (TH) 2 cells were significantly increased in RUPP rats after PIBF administration. Importantly, vasoactive pathways preproendothelin-1, nitric oxide, and soluble fms-Like tyrosine Kinase-1 (sFlt-1) were normalized in RUPP + PIBF rats compared with RUPP rats, P < 0.05. Our findings suggest that PIBF normalized IL-4/TH2 cells, which was associated with improved inflammation, fetal growth restriction, and blood pressure in the RUPP rat model of PE.
Assuntos
Antígenos de Neoplasias/farmacologia , Pressão Sanguínea/fisiologia , Inflamação/tratamento farmacológico , Progesterona/farmacologia , Útero/efeitos dos fármacos , Animais , Citocinas/metabolismo , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Feto/efeitos dos fármacos , Feto/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Isquemia/fisiopatologia , Células Matadoras Naturais/metabolismo , Placenta/metabolismo , Gravidez , Ratos , Artéria Uterina/efeitos dos fármacos , Artéria Uterina/fisiopatologia , Útero/fisiopatologiaRESUMO
To examine the therapeutic effect of Bushen Huoxue recipe (BHR) on women with thin endometrial ovulation disorder and on a rat model of kidney deficiency-related blood stasis. A total of 60 women with thin endometrial ovulation disorder was enrolled. The primary outcome of the study was the pregnancy rate three menstrual cycles after treatment. The study also examined the changes in the type and thickness of uterine artery, uterine artery pulsatility index (PI) and endometrial resistance index (RI). To establish kidney deficiency-related blood stasis in Sprague Dawley (SD) rats, an intragastric administration of hydroxyurea and a tail vein injection of Dextran were given, following with a flashing of the uterine cavity with 95% anhydrous ethanol. A combined regimen of BHR and estradiol valerate significantly increased the rate of pregnancy in women with thin endometrial ovulation disorder. The treatment was accompanied by a significant increase in endometrial thickness and decreases in uterine artery PI and endometrial RI. In rats, kidney deficiency-related blood stasis caused severe loss in endometrial architecture, thickness, and numbers of gland and blood vessel compared to the healthy SD rats. Treatment with BHR could ameliorate the endometrial damages associated with kidney deficiency-related blood stasis.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Endométrio/efeitos dos fármacos , Artéria Uterina/efeitos dos fármacos , Doenças Uterinas/tratamento farmacológico , Adulto , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Humanos , Nefropatias/complicações , Ovulação , Projetos Piloto , Gravidez , Taxa de Gravidez , Ratos Sprague-Dawley , Doenças Uterinas/etiologiaRESUMO
OBJECTIVE: To evaluate differences in Doppler parameters and pregnancy outcomes, if any, and to determine the predictive accuracy of such indices, as well as the effects of low-dose aspirin (LDA) in unexplained recurrent pregnancy loss (URPL). METHODS: An observational study was conducted at Ren Ji Hospital, Shanghai, China, from May 2015 to December 2016. The endometrial thickness, and the pulsatility index (PI), resistive index (RI), and systolic-to-diastolic ratio (S/D) values of endometrial and uterine artery blood flow were collected. Receiver operating characteristic (ROC) curve analysis was used to analyze data from URPL patients (three or more first-trimester spontaneous abortions with unknown etiology) and patients with normal fertility. A second ultrasonography examination was performed in URPL patients who had received daily LDA for 2 months. RESULTS: There were 190 URPL patients and 35 control patients. Endometrial thickness was significantly thinner in URPL patients than control patients (P=0.005). The PI, RI, and S/D values for endometrial blood flow and the mean PI, RI, and S/D values for uterine arteries were significantly higher in URPL patients (P<0.001). The predictive accuracy of the indices mentioned above were 0.660, 0.802, 0.852, 0.837, 0.784, 0.929, and 0.929, respectively. Following LDA supplementation, URPL patients showed a significant reduction in resistance to endometrial and uterine artery blood flow (P<0.001). CONCLUSION: URPL patients had impaired uterine perfusion. Doppler parameters are valuable in predicting women at high risk of URPL. LDA could be effective in improving endometrial receptivity.
Assuntos
Aborto Habitual/fisiopatologia , Aspirina/farmacologia , Endométrio/efeitos dos fármacos , Aborto Habitual/prevenção & controle , Adulto , Aspirina/administração & dosagem , Estudos de Casos e Controles , China , Endométrio/irrigação sanguínea , Endométrio/diagnóstico por imagem , Feminino , Humanos , Gravidez , Curva ROC , Ultrassonografia Doppler , Artéria Uterina/diagnóstico por imagem , Artéria Uterina/efeitos dos fármacosRESUMO
Increased O-Linked ß-N-acetylglucosamine (O-GlcNAc) is observed in several pathologies, and unbalanced O-GlcNAcylation levels favor endothelial dysfunction. Whether augmented O-GlcNAc impacts the uterine artery (UA) function and how it affects the UA during pregnancy remains to be elucidated. We hypothesized that glucosamine treatment increases O-GlcNAc, leading to uterine artery dysfunction and this effect is prevented by pregnancy. Pregnant (P) and non-pregnant (NP) Wistar rats were treated with glucosamine (300 mg/kg; i.p.) for 21 days. Concentration response-curves (CRC) to acetylcholine (in the presence or absence of L-NAME) and sodium nitroprusside were performed in UAs. In NP rats, glucosamine treatment increased O-GlcNAc expression in UAs accompanied by decreased endothelium-dependent relaxation, which was abolished by L-NAME. Endothelial nitric oxide synthase (eNOS) activity and total Akt expression were decreased by glucosamine-treatment in NP rats. Further, NP rats treated with glucosamine displayed increased glycogen synthase kinase 3 beta (GSK3ß) activation and O-GlcNAc-transferase (OGT) expression in the UA. P rats treated with glucosamine displayed decreased O-GlcNAc in UAs and it was accompanied by improved relaxation to acetylcholine, whereas eNOS and GSK3ß activity and total Akt and OGT expression were unchanged. Sodium nitroprusside-induced relaxation was not changed in all groups, indicating that glucosamine treatment led to endothelial dysfunction in NP rats. The underlying mechanism is, at least in part, dependent on Akt/GSK3ß/OGT modulation. We speculate that during pregnancy, hormonal alterations play a protective role in preventing O-GlcNAcylation-induced endothelial dysfunction in the UAs.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Glucosamina/farmacologia , Glicogênio Sintase Quinase 3 beta/fisiologia , Artéria Uterina/efeitos dos fármacos , Animais , Endotélio Vascular/fisiologia , Feminino , N-Acetilglucosaminiltransferases/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Artéria Uterina/fisiologia , Vasodilatação/efeitos dos fármacosRESUMO
To investigate the ovarian and uterine blood flow responses, hemodynamic, circulating ovarian hormones and nitric oxide (NO) after end of treatment by Folltropin. Holstein Friesian (12) cows previously synchronized with CIDR underwent Doppler ultrasound after administrating of FSH daily for 4 days in eight injections started on day 10 of the second ovulation (day -5). Oestradiol (E2), progesterone (P4) and nitric oxide (NOMs) were measured. During the follicular phase, follicle area and antrum area of the second cycle reached maximum value on the day of ovulation compared with that in the first cycle, while during the luteal phase, both showed a pattern of increase and decrease. The luteal area and total coloured area increased till day 10 in the first and second cycle. The first cycle ipsilateral ovarian artery (Ov.A) had higher pulsatility (PI) (p = .001), resistance (RI) (p = .001), peak velocity (PSV) (p = .009) and lower end-diastolic velocity (EDV) (p = .003) compared with the second cycle. The increased ipsilateral Ov.A PSV (p = .009) was accompanied by lower EDV. The first cycle ipsilateral middle uterine artery (MUA) had higher PI (p = .001) and RI (p = .001), with lower PSV (p = .001) and EDV (p = .001). It was concluded that blood flow of ovarian and middle uterine arteries changed after the end of superstimulation as the increased ipsilateral Ov. A and MUA PSVs accompanied by lower EDV and both Doppler indices that reflect the amount of ovarian and uterine blood flow waveform.
Assuntos
Bovinos/fisiologia , Hormônio Foliculoestimulante/farmacologia , Ovário/efeitos dos fármacos , Artéria Uterina/efeitos dos fármacos , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/administração & dosagem , Ciclo Menstrual/efeitos dos fármacos , Óxido Nítrico/sangue , Ovário/irrigação sanguínea , Ovário/diagnóstico por imagem , Progesterona/sangue , Superovulação/fisiologia , Ultrassonografia Doppler/veterinária , Artéria Uterina/diagnóstico por imagem , Útero/irrigação sanguínea , Útero/diagnóstico por imagemRESUMO
Incomplete maternal vascular responses to pregnancy contribute to pregnancy complications including intrauterine growth restriction (IUGR) and preeclampsia. We aimed to characterize maternal vascular dysfunction in a murine model of fetal growth restriction as an approach toward identifying targetable pathways for improving pregnancy outcomes. We utilized a murine model of late-gestation hypoxia-induced IUGR that reduced E18.5 fetal weight by 34%. Contrary to our hypothesis, uterine artery blood flow as measured in vivo by Doppler ultrasound was increased in mice housed under hypobaric hypoxia (385 mmHg; 5500 m) vs normoxia (760 mmHg; 0 m). Using wire myography, uterine arteries isolated from hypoxic mice had similar vasodilator responses to the two activators A769662 and acetylcholine as those from normoxic mice, although the contribution of an increase in nitric oxide production to uterine artery vasodilation was reduced in the hypoxic vs normoxic groups. Vasoconstrictor responses to phenylephrine and potassium chloride were unaltered by hypoxia. The levels of activated adenosine monophosphate-activated protein kinase (AMPK) were reduced with hypoxia in both the uterine artery and placenta as measured by western blot and immunohistochemistry. We concluded that the rise in uterine artery blood flow may be compensatory to hypoxia but was not sufficient to prevent fetal growth restriction. Although AMPK signaling was reduced by hypoxia, AMPK was still receptive to pharmacologic activation in the uterine arteries in which it was a potent vasodilator. Thus, AMPK activation may represent a new therapy for pregnancy complications involving reduced uteroplacental perfusion.
Assuntos
Retardo do Crescimento Fetal/fisiopatologia , Hipóxia/fisiopatologia , Circulação Placentária/fisiologia , Artéria Uterina/fisiologia , Acetilcolina/farmacologia , Animais , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Hipóxia/diagnóstico por imagem , Camundongos , Fenilefrina/farmacologia , Circulação Placentária/efeitos dos fármacos , Gravidez , Ultrassonografia Doppler , Artéria Uterina/diagnóstico por imagem , Artéria Uterina/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
The pregnancy-augmented uterine vasodilation is linked to increased AT2R (angiotensin type-2 receptor) that mediates the vasodilatory effects of angiotensin II. However, the mechanisms controlling AT2R expression during pregnancy remain unclear. Estrogens are known to play a role in vascular adaptations during pregnancy. We hypothesized that estrogen stimulates uterine artery AT2R expression via ER (estrogen receptor)-ß-dependent transcription in a pregnancy-specific endothelium-dependent manner. Plasma estradiol levels increased and peaked in late pregnancy and returned to prepregnant levels post-partum, correlating with uterine artery AT2R and ERß upregulation. Estradiol stimulated AT2R mRNA expression in endothelium-intact but not endothelium-denuded late pregnant and nonpregnant rat uterine artery ex vivo. Consistently, estradiol stimulated AT2R mRNA expression in late pregnant but not nonpregnant primary human uterine artery endothelial cells in vitro, which was abolished by ER antagonist ICI 182,780. Higher ERα protein bound to ER-responsive elements in AT2R promoter in the nonpregnant arteries whereas higher ERß bound in the pregnant state. ERα protein levels were similar but higher ERß protein levels were expressed in pregnant versus nonpregnant human uterine artery endothelial cells. Estradiol stimulation recruited ERα to the AT2R promoter in the nonpregnant state and ERß to the AT2R promoter in pregnancy; however, only ERß recruitment mediated transactivation of the AT2R reporter gene in pregnant human uterine artery endothelial cells. Estradiol-induced AT2R expression was abolished by the specific ERß (not ERα) antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) and mimicked by the specific ERß (not ERα) agonist 2,3-bis(4-Hydroxyphenyl)-propionitrile (DPN) in pregnant human uterine artery endothelial cells in vitro. This study demonstrates a novel role of pregnancy-augmented ERß in AT2R upregulation in the uterine artery and provides new insights into the mechanisms underlying uterine vascular adaptation to pregnancy.
Assuntos
Células Endoteliais/efeitos dos fármacos , Estradiol/farmacologia , Receptor beta de Estrogênio/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Artéria Uterina/efeitos dos fármacos , Animais , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Estradiol/sangue , Feminino , Gravidez , Ratos , Regulação para Cima/efeitos dos fármacos , Artéria Uterina/metabolismoRESUMO
Previous studies by our lab have established that placental-ischemia stimulated T-helper 17 cells (TH 17s) cause increased cytolytic natural killer (cNK) cell proliferation and activation during pregnancy; however, the exact mechanism is unknown. The objective of this study was to investigate the role of interlukin 17 (IL-17) in inducing cNK cell activation in pregnancy. We infused 150 pg/day of recombinant IL-17 into a subset of normal pregnant (NP) Sprague Dawley rats from gestation day (GD) 12-19 (NP+IL-17). On GD 19, mean arterial pressure (MAP), fetal and placental weights, cytokines, cNK cell activation, cytotoxic enzymes, and vascular reactivity were assessed. MAP significantly increased from 99 ± 3 mmHg in NP to 120 ± 1 mmHg in NP+IL-17 (P < 0.05). Fetal weight significantly decreased from 2.52 ± 0.04 g in NP to 2.32 ± 0.03 g in NP+IL-17 as did placental weight (NP: 0.65 ± 0.03 g; NP+IL-17: 0.54 ± 0.01 g, P < 0.05). Plasma levels of TNF-α increased to 281.4 ± 55.07 pg/mL in NP+IL-17 from 145.3 ± 16.03 pg/mL in NP (P < 0.05) while placental levels of VEGF decreased from 74.2 ± 6.48 pg/mg in NP to 54.2 ± 3.19 pg/mg in NP+IL-17. Total NK cells were increased in the placenta (NP: 14.3 ± 3.49%; NP+IL-17: 29.33 ± 2.76%, P < 0.05) as were cytolytic NK cells (NP: 3.31 ± 1.25%; NP+IL-17: 13.41 ± 1.81%, P < 0.05). A similar trend was observed in circulating NK cells. Plasma granzyme K increased from 3.55 ± 2.29 pg/mL in NP to 20.9 ± 7.76 pg/mL in NP+IL-17 (P < 0.05), and plasma granzyme B increased from 10.95 ± 0.64 pg/mL in NP to 14.9 ± 0.98 pg/mL in NP+IL-17(P < 0.05). In the placenta, both granzyme A (NP: 246.1 ± 16.7 pg/mg; NP+IL-17: 324.3 ± 15.07 pg/mg, P < 0.05) and granzyme B (NP: 15.18 ± 3.79 pg/mg; NP+IL-17: 27.25 ± 2.34 pg/mg, P < 0.05) increased in response to IL-17 infusion. Finally, vascular reactivity of uterine arteries was significantly impaired in response to IL-17 infusion. The results of this study suggest that IL-17 plays a significant role in the activation of cNK cells during pregnancy.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/fisiopatologia , Interleucina-17/administração & dosagem , Células Matadoras Naturais/efeitos dos fármacos , Artéria Uterina/efeitos dos fármacos , Animais , Pressão Sanguínea/fisiologia , Feminino , Granzimas/sangue , Placenta/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangue , Artéria Uterina/fisiopatologia , Útero/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Extravillous trophoblast (EVT) uterine artery remodeling (UAR) promotes placental blood flow, but UAR regulation is unproven. Elevating estradiol (E2) in early baboon pregnancy suppressed UAR and EVT vascular endothelial growth factor (VEGF) expression, but this did not prove that VEGF mediated this process. Therefore, our primate model of prematurely elevating E2 and contrast-enhanced ultrasound cavitation of microbubble (MB) carriers was used to deliver VEGF DNA to the placental basal plate (PBP) to establish the role of VEGF in UAR. Baboons were treated on days 25 to 59 of gestation (term, 184 days) with E2 alone or with E2 plus VEGF DNA-conjugated MBs briefly infused via a maternal peripheral vein on days 25, 35, 45, and 55. At each of these times an ultrasound beam was directed to the PBP to collapse the MBs and release VEGF DNA. VEGF DNA-labeled MBs per contrast agent was localized in the PBP but not the fetus. Remodeling of uterine arteries >25 µm in diameter on day 60 was 75% lower (P < 0.001) in E2-treated (7% ± 2%) than in untreated baboons (30% ± 4%) and was restored to normal by E2/VEGF. VEGF protein levels (signals/nuclear area) within the PBP were twofold lower (P < 0.01) in E2-treated (4.2 ± 0.9) than in untreated (9.8 ± 2.8) baboons and restored to normal by E2/VEGF (11.9 ± 1.6), substantiating VEGF transfection. Thus, VEGF gene delivery selectively to the PBP prevented the decrease in UAR elicited by prematurely elevating E2 levels, establishing the role of VEGF in regulating UAR in vivo during primate pregnancy.
Assuntos
Estradiol/farmacologia , Placenta/efeitos dos fármacos , Artéria Uterina/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Feminino , Papio , Placenta/metabolismo , Gravidez , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismoRESUMO
Maternal engineered nanomaterial (ENM) inhalation is associated with uterine vascular impairments and endocrine disruption that may lead to altered gestational outcomes. We have shown that nano-titanium dioxide (nano-TiO2) inhalation impairs endothelium-dependent uterine arteriolar dilation in pregnant rats. However, the mechanism underlying this dysfunction is unknown. Due to its role as a potent vasoconstrictor and essential reproductive hormone, we examined how kisspeptin is involved in nano-TiO2-induced vascular dysfunction and placental efficiency. Pregnant Sprague Dawley rats were exposed (gestational day [GD] 10) to nano-TiO2 aerosols (cumulative dose = 525 ± 16 µg; n = 8) or sham exposed (n = 6) and sacrificed on GD 20. Plasma was collected to evaluate estrogen (E2), progesterone (P4), prolactin (PRL), corticosterone (CORT), and kisspeptin. Pup and placental weights were measured to calculate placental efficiency (grams fetus/gram placental). Additionally, pressure myography was used to determine uterine artery vascular reactivity. Contractile responses were assessed via cumulative additions of kisspeptin (1 × 10-9 to 1 × 10-4 M). Estrogen was decreased at GD 20 in exposed (11.08 ± 3 pg/ml) versus sham-control rats (66.97 ± 3 pg/ml), whereas there were no differences in P4, PRL, CORT, or kisspeptin. Placental weights were increased in exposed (0.99 ± 0.03 g) versus sham-control rats (0.70 ± 0.04 g), whereas pup weights (4.01 ± 0.47 g vs 4.15 ± 0.15 g) and placental efficiency (4.5 ± 0.2 vs 6.4 ± 0.5) were decreased in exposed rats. Maternal ENM inhalation exposure augmented uterine artery vasoconstrictor responses to kisspeptin (91.2%±2.0 vs 98.6%±0.10). These studies represent initial evidence that pulmonary maternal ENM exposure perturbs the normal gestational endocrine vascular axis via a kisspeptin-dependent mechanism, and decreased placental, which may adversely affect health outcomes.
Assuntos
Feto/efeitos dos fármacos , Kisspeptinas/fisiologia , Exposição Materna/efeitos adversos , Titânio/toxicidade , Artéria Uterina/efeitos dos fármacos , Animais , Feminino , Hormônios Esteroides Gonadais/sangue , Exposição por Inalação , Kisspeptinas/sangue , Nanopartículas , Placenta/efeitos dos fármacos , Placenta/patologia , Gravidez , Ratos , Ratos Sprague-Dawley , Artéria Uterina/fisiologiaRESUMO
OBJECTIVE: Changes in maternal serum concentration of placental growth factor (PlGF) and vascular response to intravascular infusion of Angiotensin II (Ang II) follow a bell-shaped curve pattern during gestation. This study evaluates the effects of PlGF and soluble vascular endothelial growth factor receptor-1 (sFlt-1) on responses of human uterine arteries (UA) to Ang II. DESIGN: Experimental. SETTING: Baylor College of Medicine and Texas Children's Hospital-Pavilion for Women. SAMPLE: Uterine arteries samples (n = 14) were obtained from normotensive women undergoing caesarean hysterectomy at ≥32 weeks. METHODS: Uterine arteries rings were incubated with (1) Krebs solution; (2) PlGF at 1.45, 14.5, and 500 pg/ml; (3) sFlt-1 at 2 ng/ml; and (4) a combination of sFlt-1, and PlGF. Dose-contraction responses to Ang II were determined in UA rings incubated in the above-mentioned conditions. Responses were also measured in presence of L-NAME or inhibitors of endothelium-derived hyperpolarising factor: apamine and charybdotoxin. The t-test was used for comparisons. MAIN OUTCOME MEASURE: Changes in vascular reactivity of UA rings. RESULTS: PlGF blunted (P = 0.03) and sFlt-1 increased (P <0.01) the UA maximum responses to Ang II. A combination of sFlt-1 and PlGF blunted UA responses to Ang II (P < 0.05). l-NAME, apamine, and charybdotoxin reversed the relaxation effects of PlGF on UA responses to Ang II (P < 0.05). CONCLUSIONS: PlGF contributes to the blunted vascular response to Angiotensin II during normotensive pregnancies and sFlt-1 appears to attenuate this effect. PlGF and sFlt-1 may contribute to the regulation of vascular tone during pregnancy by altering the vascular response to Angiotensin II. FUNDING: Baylor College of Medicine. TWEETABLE ABSTRACT: Placental growth factor and soluble vascular endothelial growth factor receptor-1 modulate the uterine artery response to Angiotensin II in normotensive pregnant women.
Assuntos
Angiotensina II/farmacologia , Fator de Crescimento Placentário/metabolismo , Artéria Uterina/efeitos dos fármacos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Vasoconstritores/farmacologia , Adulto , Pressão Sanguínea , Feminino , Humanos , GravidezRESUMO
BACKGROUND: The efficacy of therapy for cervical cancer is related to the alteration of multiple molecular events and signaling networks during treatment. The aim of this study was to evaluate gene expression alterations in advanced cervical cancers before- and after-trans-uterine arterial chemoembolization- (TUACE). METHODS: Gene expression patterns in three squamous cell cervical cancers before- and after-TUACE were determined using microarray technique. Changes in AKAP12 and CA9 genes following TUACE were validated by quantitative real-time PCR. RESULTS: Unsupervised cluster analysis revealed that the after-TUACE samples clustered together, which were separated from the before-TUACE samples. Using a 2-fold threshold, we identified 1131 differentially expressed genes that clearly discriminate after-TUACE tumors from before-TUACE tumors, including 209 up-regulated genes and 922 down-regulated genes. Pathway analysis suggests these genes represent diverse functional categories. Results from real-time PCR confirmed the expression changes detected by microarray. CONCLUSIONS: Gene expression signature significantly changes during TUACE therapy of cervical cancer. Theses alterations provide useful information for the development of novel treatment strategies for cervical cancers on the molecular level.
Assuntos
Proteínas de Ancoragem à Quinase A/genética , Antígenos de Neoplasias/genética , Anidrase Carbônica IX/genética , Carcinoma de Células Escamosas/genética , Proteínas de Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Reação em Cadeia da Polimerase em Tempo Real , Artéria Uterina/efeitos dos fármacos , Artéria Uterina/patologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapiaRESUMO
OBJECTIVES: The objective of this study is to evaluate agreement between PlGF and sFlt-1/PlGF ratio tests and compare their predictive accuracy for pre-eclampsia in high-risk women. Also, to examine for associations of abnormal PlGF or sFlt-1/PlGF ratio with abnormal uterine artery Doppler and platelet response to aspirin. METHODS: Prospective cohort study, 150 pregnant women at high risk of pre-eclampsia prescribed 75 mg aspirin daily. Uterine artery Dopplers were assessed at 20+0-23+6 weeks. At 33+0-35+6 weeks platelet function aspirin metabolites, PlGF and the sFlt-1/PlGF ratio were measured. OUTCOME: Measures were all pre-eclampsia and pre-eclampsia requiring delivery prior to 37 weeks. RESULTS: Overall percent agreement was 89.3% for PlGF tests but 74.7-78% for PlGF tests and the sFlt-1/PlGF ratio. AUCs were 0.70-0.75 for prediction of any pre-eclampsia and 0.92-0.99 for preterm pre-eclampsia. We found a significant association between abnormal PlGF or sFlt-1/PlGF ratio and abnormal uterine artery Doppler (χ2 5.47, p = .019), but no association with platelet response to aspirin (χ2 0.12, p = .913). There were no associations between suboptimal aspirin adherence and either abnormal angiogenic markers or uterine artery Dopplers (χ2 0.144, 0.038, p = .704, .846, respectively). CONCLUSIONS: There was good agreement between PlGF tests and limited agreement between PlGF tests and the sFlt-1/PlGF ratio. All tests have heightened predictive accuracy for preterm pre-eclampsia. Abnormal PlGF or sFlt-1/PlGF ratio relates to abnormal uterine artery Doppler but not platelet response to aspirin.