RESUMO
Preeclampsia is a multisystem hypertensive disorder of pregnancy that remains one of the leading causes of maternal and perinatal morbidity and mortality worldwide. The widespread maternal endothelial dysfunction that underlies preeclampsia is thought to arise from excessive placental production of various factors combined with enhanced oxidative stress. While previous studies have reported elevated activin A in women diagnosed with preeclampsia, whether activin A can cause vascular dysfunction has not yet been thoroughly investigated. Here, we demonstrated that different subtypes of activin A receptors were localised to the endothelial and smooth muscle cells of mouse and human aortae. Then, the aorta of healthy female C57Bl6J mice (n = 8) were incubated for 24 h in various concentrations of recombinant activin A to mimic early pregnancy (5 ng/mL), late pregnancy (20 ng/mL) and preeclampsia (50 ng/mL). Vascular reactivity as assessed by wire myography revealed that only the preeclamptic level of activin A impaired agonist-mediated endothelium-dependent relaxation by reducing the vasodilator prostanoid contribution to relaxation. However, agonist-mediated endothelium-independent mechanisms were unaffected. Further investigations carried out on human aortic endothelial cells suggested that the impairment of aorta relaxation could also be driven by increased endothelial cell permeability, and decreased cell viability, adherence and proliferation. This is the first direct evidence to show that activin A can induce endothelial dysfunction in whole blood vessels, suggesting that at high circulating levels it may contribute to the widespread endothelial dysfunction in women with preeclampsia.
Assuntos
Células Endoteliais , Pré-Eclâmpsia , Ativinas , Animais , Aorta , Endotélio Vascular , Feminino , Humanos , Camundongos Endogâmicos C57BL , Placenta , Pré-Eclâmpsia/etiologia , GravidezRESUMO
The formyl peptide receptor (FPR) family are a group of G-protein coupled receptors that play an important role in the regulation of inflammatory processes. It is well-established that activation of FPRs can have cardioprotective properties. Recently, more stable small-molecule FPR1/2 agonists have been described, including both Compound 17b (Cmpd17b) and Compound 43 (Cmpd43). Both agonists activate a range of signals downstream of FPR1/2 activation in human-engineered FPR-expressing cells, including ERK1/2 and Akt. Importantly, Cmpd17b (but not Cmpd43) favours bias away from intracellular Ca2+ mobilisation in this context, which has been associated with greater cardioprotection in response to Cmpd17b over Cmpd43. However, it is unknown whether these FPR agonists impact vascular physiology and/or elicit vasoprotective effects in the context of diabetes. First, we localized FPR1 and FPR2 receptors predominantly in vascular smooth muscle cells in the aortae of male C57BL/6 mice. We then analysed the vascular effects of Cmpd17b and Cmpd43 on the aorta using wire-myography. Cmpd17b but not Cmpd43 evoked a concentration-dependent relaxation of the mouse aorta. Removal of the endothelium or blockade of endothelium-derived relaxing factors using pharmacological inhibitors had no effect on Cmpd17b-evoked relaxation, demonstrating that its direct vasodilator actions were endothelium-independent. In aortae primed with elevated K+ concentration, increasing concentrations of CaCl2 evoked concentration-dependent contraction that is abolished by Cmpd17b, suggesting the involvement of the inhibition of Ca2+ mobilisation via voltage-gated calcium channels. Treatment with Cmpd17b for eight weeks reversed endothelial dysfunction in STZ-induced diabetic aorta through the upregulation of vasodilator prostanoids. Our data indicate that Cmpd17b is a direct endothelium-independent vasodilator, and a vasoprotective molecule in the context of diabetes.
Assuntos
Anexina A1/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Aorta/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Substâncias Protetoras/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Formil Peptídeo/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Estreptozocina , Vasodilatadores/farmacologiaRESUMO
(1) Background: There is increasing understanding of the potential health benefits of cruciferous vegetables. In particular sulforaphane (SFN), found in broccoli, and its metabolites sulforaphane-glutathione (SFN-GSH), sulforaphane-cysteine (SFN-Cys), sulforaphane cysteine-glycine (SFN-CG) and sulforaphane-N-acetyl-cysteine (SFN-NAC) have potent antioxidant effects that may offer therapeutic value. Clinical investigation of sulforaphane as a therapeutic antioxidant requires a sensitive and high throughput process for quantification of sulforaphane and metabolites; (2) Methods: We collected plasma samples from healthy human volunteers before and for eight hours after consumption of a commercial broccoli extract supplement rich in sulforaphane. A rapid and sensitive method for quantification of sulforaphane and its metabolites in human plasma using Liquid Chromatography-Mass Spectrometry (LC-MS) has been developed; (3) Results: The LC-MS analytical method was validated at concentrations ranging between 3.9 nM and 1000 nM for SFN-GSH, SFN-CG, SFN-Cys and SFN-NAC and between 7.8 nM and 1000 nM in human plasma for SFN. The method displayed good accuracy (1.85%-14.8% bias) and reproducibility (below 9.53 %RSD) including low concentrations 3.9 nM and 7.8 nM. Four SFN metabolites quantitation was achieved using external standard calibration and in SFN quantitation, SFN-d8 internal standardization was used. The reported method can accurately quantify sulforaphane and its metabolites at low concentrations in plasma; (4) Conclusions: We have established a time- and cost-efficient method of measuring sulforaphane and its metabolites in human plasma suitable for high throughput application to clinical trials.
Assuntos
Isotiocianatos/sangue , Cromatografia Líquida/métodos , Humanos , Isotiocianatos/farmacocinética , Espectrometria de Massas/métodos , Reprodutibilidade dos Testes , SulfóxidosRESUMO
Early maternal vascular adaptations to pregnancy are predominantly driven by changes in vascular tone, reactivity, and remodeling. Failure of the maternal systemic vasculature to adapt sufficiently can lead to serious complications of pregnancy. The hormone relaxin is widely recognized for its contribution to the essential renal and systemic hemodynamic adaptations in early pregnancy through direct actions on the maternal vasculature. Studies in relaxin gene knockout mice revealed that endogenous relaxin is not only a "pregnancy hormone" but has pleiotropic actions in various tissues in males and non-pregnant females. There is strong interest in relaxin's actions in the vasculature and its utility in the treatment of vascular diseases. Relaxin treatment in rodents for 2-5 days or acute intravenous injection enhances endothelium-dependent relaxation and decreases myogenic tone in resistance arteries. These vascular actions are prolonged, even in the absence of circulating relaxin, and are underpinned by the production of endothelium-derived relaxing factors including nitric oxide, endothelium-derived hyperpolarization, and prostacyclin. Relaxin is also capable of remodeling the vascular wall in a variety of blood vessels in disease conditions. Lessons learned in pregnancy research have aided studies investigating the potential therapeutic potential of relaxin in cardiovascular disease.
Assuntos
Gravidez , Relaxina/fisiologia , Animais , Vasos Sanguíneos/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Relaxina/deficiência , Relaxina/uso terapêutico , Vasodilatação/efeitos dos fármacosRESUMO
Preeclampsia is a pregnancy-specific disorder, primarily characterized by new-onset hypertension in combination with a variety of other maternal or fetal signs. The pathophysiological mechanisms underlying the disease are still not entirely clear. Systemic maternal vascular dysfunction underlies the clinical features of preeclampsia. It is a result of oxidative stress and the actions of excessive anti-angiogenic factors, such as soluble fms-like tyrosine kinase, soluble endoglin, and activin A, released by a dysfunctional placenta. The vascular dysfunction then leads to impaired regulation and secretion of relaxation factors and an increase in sensitivity/production of constrictors. This results in a more constricted vasculature rather than the relaxed vasodilated state associated with normal pregnancy. Currently, the only effective "treatment" for preeclampsia is delivery of the placenta and therefore the baby. Often, this means a preterm delivery to save the life of the mother, with all the attendant risks and burdens associated with fetal prematurity. To lessen this burden, there is a pressing need for more effective treatments that target the maternal vascular dysfunction that underlies the hypertension. This review details the vascular effects of key drugs undergoing clinical assessment as potential treatments for women with preeclampsia.
RESUMO
The peptide hormone relaxin has numerous roles both within and independent of pregnancy and is often thought of as a "pleiotropic hormone." Relaxin targets several tissues throughout the body, and has many functions associated with extracellular matrix remodeling and the vasculature. This review considers the potential therapeutic applications of relaxin in cervical ripening, in vitro fertilization, preeclampsia, acute heart failure, ischemia-reperfusion, and cirrhosis. We first outline the animal models used in preclinical studies to progress relaxin into clinical trials and then discuss the findings from these studies. In many cases, the positive outcomes from preclinical animal studies were not replicated in human clinical trials. Therefore, the focus of this review is to evaluate the various animal models used to develop relaxin as a potential therapeutic and consider the limitations that must be addressed in future studies. These include the use of human relaxin in animals, duration of relaxin treatment, and the appropriateness of the clinical conditions being considered for relaxin therapy.
Assuntos
Relaxina/farmacologia , Relaxina/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hepatopatias/tratamento farmacológico , Gravidez , Relaxina/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológicoRESUMO
Preeclampsia affects up to 8% of pregnancies worldwide and is a leading cause of both maternal and fetal morbidity and mortality. Our current understanding of the cause(s) of preeclampsia is far from complete, and the lack of a single reliable animal model that recapitulates all aspects of the disease further confounds our understanding. This is partially due to the heterogeneous nature of the disease, coupled with our evolving understanding of its etiology. Nevertheless, animal models are still highly relevant and useful tools that help us better understand the pathophysiology of specific aspects of preeclampsia. This review summarizes the various types and characteristics of animal models used to study preeclampsia, highlighting particular features of these models relevant to clinical translation. This review points out the strengths and limitations of these models to illustrate the importance of using the appropriate model depending on the research question.
Assuntos
Pressão Sanguínea , Pré-Eclâmpsia/fisiopatologia , Pesquisa Translacional Biomédica/métodos , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Feminino , Humanos , Circulação Placentária , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/etiologia , Gravidez , Fatores de Risco , Transdução de Sinais , Especificidade da EspécieRESUMO
Relaxin regulates cervical extracellular matrix (ECM) remodelling during pregnancy by modifying collagen and other ECM molecules by unknown mechanisms. We hypothesised that abnormal collagen remodelling in the cervix of pregnant relaxin-deficient (Rln1-/-) mice is due to excessive collagen (Col1a1 and Col3a1) and decreased matrix metalloproteinases (Mmp2, Mmp9, Mmp13 and Mmp7) and oestrogen receptors (Esr1 and Esr2). Quantitative polymerase chain reaction, gelatinase zymography, MMP activity assays and histological staining evaluated changes in ECM in pregnant wildtype (Rln1+/+) and Rln1-/- mice. Cervical Col1a1, Col3a1 and total collagen increased in Rln1-/- mice and were higher at term compared with Rln1+/+ mice. This was not correlated with a decrease in gelatinase (Mmp2, Mmp9) expression or activity, Mmp7 or Mmp13 expression, which were all significantly higher in Rln1-/- mice. In late pregnancy, circulating MMP2 and MMP9 were unchanged. Esr1 expression was highest in Rln1+/+ and Rln1-/- mice in late pregnancy, coinciding with a decrease in Esr2 in Rln1+/+ but not Rln1-/- mice. The relaxin receptor (Rxfp1) decreased slightly in late-pregnant Rln1+/+ mice, but was significantly higher in Rln1-/- mice. In summary, relaxin deficiency results in increased cervical collagen in late pregnancy, which is not explained by a reduction in Mmp expression or activity or decreased Rxfp1. However, an imbalance between Esr1 and Esr2 may be involved.
Assuntos
Colo do Útero/metabolismo , Matriz Extracelular/metabolismo , Metaloproteinases da Matriz/metabolismo , Relaxina/genética , Animais , Feminino , Gelatinases/genética , Gelatinases/metabolismo , Metaloproteinases da Matriz/genética , Camundongos , Camundongos Knockout , Gravidez , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/genética , Receptores de Peptídeos/metabolismo , Relaxina/metabolismoRESUMO
This study sought to characterize depressive symptoms among mothers in Latino farmworker families, determine if maternal depression increases children's risk of obesity, and ascertain whether relevant risk factors such as physical activity, diet, and feeding style mediate this relationship. Mothers from 248 families completed the 10-item Center for Epidemiologic Studies Depression Scale 9 times over a 2-year period. Four distinct patterns were used to describe mothers: few symptoms, moderate episodic symptoms, severe episodic symptoms, and chronic symptoms. Approximately two-thirds of women experienced moderate symptoms of depression at least once. Children of mothers fitting each pattern were compared. At the end of the study, children of mothers with severe episodic and chronic symptoms were significantly more likely to be overweight and obese than children of mothers with few symptoms (p < .05). After controlling for covariates, differences in weight status for children of mothers with severe episodic symptoms remained significant. Children of mothers with either moderate episodic or chronic symptoms were fed in a less responsive fashion (p < .05), and children of chronically symptomatic mothers had lower diet quality (p < .01). Although nonresponsive feeding has been linked to childhood obesity, in this analysis, feeding style did not mediate the relationship between maternal depression and diet quality. Elevated levels of depressive symptoms are common in this population, and those symptoms, especially when severe or chronic in nature, may increase children's risk of obesity. Additional research is needed to characterize the pathways through which maternal depression influences children's weight.
Assuntos
Peso Corporal/fisiologia , Depressão/epidemiologia , Fazendeiros/estatística & dados numéricos , Hispânico ou Latino/estatística & dados numéricos , Mães/estatística & dados numéricos , Adolescente , Adulto , Pré-Escolar , Comportamento Alimentar , Feminino , Humanos , Estudos Longitudinais , Masculino , North Carolina/epidemiologia , Obesidade Infantil , Adulto JovemRESUMO
BACKGROUND: Short-term IV sRLX (recombinant human relaxin-2) infusion enhances endothelium-dependent relaxation in mesenteric arteries. This is initially underpinned by increased NO followed by a transition to prostacyclin. The effects of short-term IV sRLX treatment on pressure-induced myogenic tone and vascular remodeling in these arteries are unknown. Therefore, we investigated the effects of sRLX infusion on pressure-induced myogenic tone and passive mechanical wall properties in mesenteric arteries. METHODS: Mesenteric artery myogenic tone and passive mechanics were examined after 48-hours and 10-days infusion of sRLX. Potential mechanisms of action were assessed by pressure myography, qPCR, and Western blot analysis. RESULTS: Neither 48-hours nor 10-days sRLX treatment had significant effects on myogenic tone, passive arterial wall stiffness, volume compliance, or axial lengthening. However, in 48-hours sRLX -treated rats, incubation with the NO synthase blocker L-NAME significantly increased myogenic tone (P<.05 vs placebo), demonstrating an increased contribution of NO to the regulation of myogenic tone. eNOS dimerization, but not phosphorylation, was significantly upregulated in the arteries of sRLX -treated rats. CONCLUSION: In mesenteric arteries, 48-hours sRLX treatment upregulates the role of NO in the regulation of myogenic tone by enhancing eNOS dimerization, without altering overall myogenic tone or vascular remodeling.
Assuntos
Artérias Mesentéricas/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Relaxina/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Multimerização Proteica , Ratos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Relaxina/administração & dosagem , Fatores de TempoRESUMO
The peptide relaxin has gained considerable attention as a new vasoactive drug, largely through its beneficial therapeutic effects in cardiovascular disease. In this study, we tested the hypothesis that relaxin treatment alleviates systemic vascular dysfunction characteristic of hypertensive diseases of pregnancy. We investigated vascular effects and mechanisms of relaxin action in (i) pregnant relaxin-deficient (Rln-/-) mice with enhanced responses to angiotensin II (AngII) and (ii) arteries pre-incubated ex vivo in trophoblast conditioned media (TCM) to induce endothelial dysfunction. Pregnant Rln-/- mice received 0.5 µg/h recombinant human H2 relaxin (rhRLX: n = 5) or placebo (20 nM sodium acetate; n = 7) subcutaneously via osmotic minipumps for 5 days prior to gestational day 17.5. This treatment protocol significantly reduced AngII-mediated contraction of mesenteric arteries and increased plasma 6-keto prostaglandin F1α. These vascular effects were endothelium independent and likely involve smooth muscle-derived vasodilator prostanoids. In the second study, mesenteric arteries were incubated ex vivo for 24 h at 37°C in TCM, which contained high levels of soluble Flt-1 (>20 ng/ml) and soluble Eng (>1 ng/ml). TCM incubation caused significant reduction in endothelium-dependent relaxation and increased sensitivity to AngII. Co-incubation of arteries with rhRLX for 24 h (n = 6-16/treatment) prevented endothelial dysfunction but had no effect on AngII-mediated contraction. In conclusion, relaxin treatment prevents and/or reverses vascular dysfunction in mesenteric arteries, but acts through different vascular pathways depending on duration of relaxin treatment and type of vascular dysfunction. Overall, our data suggest that relaxin is a potential therapeutic to alleviate maternal systemic vascular dysfunction associated with hypertensive diseases in pregnant women.
Assuntos
Angiotensina II/farmacologia , Endotélio Vascular/efeitos dos fármacos , Relaxina/farmacologia , Vasoconstrição/fisiologia , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Knockout , GravidezRESUMO
OBJECTIVE: Adiposity rebound (AR) or BMI (body mass index) rebound refers to the increase in BMI following the minimum BMI in early childhood. Early AR (before age 5) is predictive of adult obesity. To determine how 4 domains - demographics, maternal BMI, food security, and behavioral characteristics - may affect timing of AR. STUDY DESIGN: A total of 248 children, ages 2.5-3.5 years, in Latino farmworker families in North Carolina were examined at baseline and every 3 months for 2 years. BMI was plotted serially for each child and the onset of BMI rebound was determined by visual inspection of the graphs. Given the ages of the children, all rebounds were detected before age 5 years and were deemed "early," whereas other children were classified as "nonrebounders." Classes were then compared in terms of the 4 domains with the use of bivariate analyses and linear mixed models. RESULTS: A total of 131 children demonstrated early rebound, 59 children were nonrebounders, and a further 35 had inconclusive data. Parents of early rebounders were less likely to have documentation permitting legal residence in the US. Mothers of early rebounders were on average 3 BMI units heavier. Sex, household food security, diet quality, caloric intake, and daily activity did not differ between classes. In multivariable analysis, female sex, limited maternal education, increased maternal BMI, and increased caloric intake were significant predictors of early rebound. CONCLUSION: High maternal BMI was the strongest predictor of early BMI rebound, but increased caloric intake also was significant. Limiting excess calories could delay premature AR and lower the risk of future obesity.
Assuntos
Adiposidade , Índice de Massa Corporal , Obesidade/epidemiologia , Fatores Etários , Pré-Escolar , Feminino , Humanos , Estudos Longitudinais , Masculino , Fatores de RiscoRESUMO
Pre-eclampsia (PE) is a leading cause of maternal and fetal death, characterised by an imbalance of placental growth factors and hypertension at >20 weeks gestation. Impaired maternal systemic vascular adaptations and fetal growth restriction are features of both PE and pregnant relaxin-deficient (Rln-/-) mice. The aim of the present study was to investigate whether these phenotypes in Rln-/- mice are associated with abnormal placental growth factor expression, increased soluble fms-like tyrosine kinase-1 (sFlt-1), proteinuria and/or hypertension during pregnancy. In addition, we examined relaxin and relaxin receptor (relaxin/insulin like family peptide receptor 1 (RXFP1)) mRNA expression in placentas of women with PE. There was no significant difference in placental vascular endothelial growth factor A (VegfA) and placenta growth factor (Plgf) gene expression between Rln-/- and wild-type mice. Circulating plasma sFlt-1 concentrations in pregnant mice of both genotypes and ages were increased compared with non-pregnant mice but were lower in younger pregnant Rln-/- mice compared with aged-matched Rln+/+ mice. Aged pregnant Rln-/- mice had higher urinary albumin:creatinine ratios compared with age-matched Rln+/+ mice, indicative of proteinuria. Systolic and diastolic blood pressures did not differ between genotypes. In addition, PE in women was not associated with altered placental mRNA expression of RLN2 or RXFP1 at term. Overall, the data demonstrate that pregnant Rln-/- mice do not have the typical characteristics of PE. However, these mice show evidence of proteinuria, but we suggest that this results from systemic renal vascular dysfunction before pregnancy.
Assuntos
Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Proteinúria/metabolismo , Relaxina/metabolismo , Animais , Pressão Sanguínea/fisiologia , Feminino , Humanos , Camundongos , Camundongos Knockout , Fator de Crescimento Placentário/genética , Fator de Crescimento Placentário/metabolismo , Pré-Eclâmpsia/genética , Gravidez , Proteinúria/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/genética , Receptores de Peptídeos/metabolismo , Relaxina/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Commonly used methods to assess cognition, such as direct observation, self-report, or neuropsychological testing, have significant limitations. Therefore, a novel tablet computer-based video simulation was created with the goal of being valid, reliable, and easy to administer. The design and implementation of the SIMBAC (Simulation-Based Assessment of Cognition) instrument is described in detail, as well as informatics "lessons learned" during development. RESULTS: The software emulates 5 common instrumental activities of daily living (IADLs) and scores participants' performance. The modules were chosen by a panel of geriatricians based on relevance to daily functioning and ability to be modeled electronically, and included facial recognition, pairing faces with the correct names, filling a pillbox, using an automated teller machine (ATM), and automatic renewal of a prescription using a telephone. Software development included three phases 1) a period of initial design and testing (alpha version), 2) pilot study with 10 cognitively normal and 10 cognitively impaired adults over the age of 60 (beta version), and 3) larger validation study with 162 older adults of mixed cognitive status (release version). Results of the pilot study are discussed in the context of refining the instrument; full results of the validation study are reported in a separate article. In both studies, SIMBAC reliably differentiated controls from persons with cognitive impairment, and performance was highly correlated with Mini Mental Status Examination (MMSE) score. Several informatics challenges emerged during software development, which are broadly relevant to the design and use of electronic assessment tools. Solutions to these issues, such as protection of subject privacy and safeguarding against data loss, are discussed in depth. Collection of fine-grained data (highly detailed information such as time spent reading directions and the number of taps on screen) is also considered. CONCLUSIONS: SIMBAC provides clinicians direct insight into whether subjects can successfully perform selected cognitively intensive activities essential for independent living and advances the field of cognitive assessment. Insight gained from the development process could inform other researchers who seek to develop software tools in health care.
Assuntos
Atividades Cotidianas , Disfunção Cognitiva/diagnóstico , Diagnóstico por Computador/métodos , Avaliação Geriátrica/métodos , Testes Neuropsicológicos , Idoso , Computadores de Mão , Humanos , Projetos PilotoRESUMO
Pregnancy is associated with reduced peripheral vascular resistance, underpinned by changes in endothelial and smooth muscle function. Failure of the maternal vasculature to adapt correctly leads to serious pregnancy complications, such as preeclampsia. The peptide hormone relaxin regulates the maternal renal vasculature during pregnancy; however, little is known about its effects in other vascular beds. This study tested the hypothesis that functional adaptation of the mesenteric and uterine arteries during pregnancy will be compromised in relaxin-deficient (Rln(-/-)) mice. Smooth muscle and endothelial reactivity were examined in small mesenteric and uterine arteries of nonpregnant (estrus) and late-pregnant (day 17.5) wild-type (Rln(+/+)) and Rln(-/-) mice using wire myography. Pregnancy per se was associated with significant reductions in contraction to phenylephrine, endothelin-1, and ANG II in small mesenteric arteries, while sensitivity to endothelin-1 was reduced in uterine arteries of Rln(+/+) mice. The normal pregnancy-associated attenuation of ANG II-mediated vasoconstriction in mesenteric arteries did not occur in Rln(-/-) mice. This adaptive failure was endothelium-independent and did not result from altered expression of ANG II receptors or regulator of G protein signaling 5 (Rgs5) or increases in reactive oxygen species generation. Inhibition of nitric oxide synthase with l-NAME enhanced ANG II-mediated contraction in mesenteric arteries of both genotypes, whereas blockade of prostanoid production with indomethacin only increased ANG II-induced contraction in arteries of pregnant Rln(+/+) mice. In conclusion, relaxin deficiency prevents the normal pregnancy-induced attenuation of ANG II-mediated vasoconstriction in small mesenteric arteries. This is associated with reduced smooth muscle-derived vasodilator prostanoids.
Assuntos
Adaptação Fisiológica/fisiologia , Angiotensina II/metabolismo , Artérias Mesentéricas/fisiologia , Prenhez , Relaxina/metabolismo , Animais , Feminino , Regulação da Expressão Gênica/fisiologia , Camundongos , Camundongos Knockout , Gravidez , Prenhez/fisiologia , Receptores de Angiotensina/fisiologia , Relaxina/genética , Artéria Uterina/fisiologia , Vasodilatação/fisiologiaRESUMO
BACKGROUND: Extensive uterine adaptations, including angiogenesis, occur prior to implantation in early pregnancy and are potentially regulated by the peptide hormone relaxin. This was investigated in two studies. First, we took a microarray approach using human endometrial stromal (HES) cells treated with relaxin in vitro to screen for target genes. Then we aimed to investigate whether or not relaxin deficiency in mice affected uterine expression of representative genes associated with angiogenesis and uterine remodeling, and also blood vessel proliferation in the pre-implantation mouse endometrium. METHODS: Normal HES cells were isolated and treated with recombinant human relaxin (10 ng/ml) for 24 h before microarray analysis. Reverse transcriptase PCR was used to analyze gene expression of relaxin and its receptor (Rxfp1) in ovaries and uteri; quantitative PCR was used to analyze steroid receptor, angiogenesis and extracellular matrix remodeling genes in the uteri of wild type (Rln+/+) and Rln-/- mice on days 1-4 of pregnancy. Immunohistochemistry localized endometrial endothelial cell proliferation and mass spectrometry measured steroid hormones in the plasma. RESULTS: Microarray analysis identified 63 well-characterized genes that were differentially regulated in HES cells after relaxin treatment. Expression of some of these genes was increased in the uterus of Rln+/+ mice by day 4 of pregnancy. There was significantly higher vascular endothelial growth factor A (VegfA), estrogen receptor 1 (Esr1), progesterone receptor (Pgr), Rxfp1, egl-9 family hypoxia-inducible factor 1 (Egln1), hypoxia inducible factor 1 alpha (Hif1α), matrix metalloproteinase 14 (Mmp14) and ankryn repeat domain 37 (Ankrd37) in Rln-/- compared to Rln+/+ mice on day 1. Progesterone receptor expression and plasma progesterone levels were higher in Rln-/- mice compared to Rln+/+ mice. However, endometrial angiogenesis was not advanced as pre-implantation endothelial cell proliferation did not differ between genotypes. CONCLUSIONS: Relaxin treatment modulates expression of a variety of angiogenesis-related genes in HES cells. However, despite accelerated uterine gene expression of steroid receptor, progesterone and angiogenesis and extracellular matrix remodeling genes in Rln-/- mice, there was no impact on angiogenesis. We conclude that although relaxin deficiency results in phenotypic changes in the pre-implantation uterus, endogenous relaxin does not play a major role in pre-implantation angiogenesis in the mouse uterus.
Assuntos
Neovascularização Fisiológica/genética , Relaxina/fisiologia , Animais , Proliferação de Células , Endométrio/citologia , Endométrio/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Relaxina/farmacologia , Células Estromais , Útero/citologia , Útero/metabolismoRESUMO
PURPOSE: User-generated content on social media sites, such as health-related online forums, offers researchers a tantalizing amount of information, but concerns regarding scientific application of such data remain. This paper compares and contrasts symptom cluster patterns derived from messages on a breast cancer forum with those from a symptom checklist completed by breast cancer survivors participating in a research study. METHODS: Over 50,000 messages generated by 12,991 users of the breast cancer forum on MedHelp.org were transformed into a standard form and examined for the co-occurrence of 25 symptoms. The k-medoid clustering method was used to determine appropriate placement of symptoms within clusters. Findings were compared with a similar analysis of a symptom checklist administered to 653 breast cancer survivors participating in a research study. RESULTS: The following clusters were identified using forum data: menopausal/psychological, pain/fatigue, gastrointestinal, and miscellaneous. Study data generated the clusters: menopausal, pain, fatigue/sleep/gastrointestinal, psychological, and increased weight/appetite. Although the clusters are somewhat different, many symptoms that clustered together in the social media analysis remained together in the analysis of the study participants. Density of connections between symptoms, as reflected by rates of co-occurrence and similarity, was higher in the study data. CONCLUSIONS: The copious amount of data generated by social media outlets can augment findings from traditional data sources. When different sources of information are combined, areas of overlap and discrepancy can be detected, perhaps giving researchers a more accurate picture of reality. However, data derived from social media must be used carefully and with understanding of its limitations.
Assuntos
Neoplasias da Mama/complicações , Indicadores Básicos de Saúde , Autorrelato , Mídias Sociais , Avaliação de Sintomas/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/psicologia , Lista de Checagem , Análise por Conglomerados , Feminino , Humanos , Pessoa de Meia-Idade , Qualidade de VidaRESUMO
Erectile dysfunction (ED) is an extremely prevalent condition which significantly impacts quality of life. The rapid increase of ED in recent decades suggests the existence of unidentified environmental risk factors contributing to this condition. Endocrine Disrupting Chemicals (EDCs) are one likely candidate, given that development and function of the erectile tissues are hormonally dependent. We use the estrogenic-EDC diethylstilbestrol (DES) to model how widespread estrogenic-EDC exposure may impact erectile function in humans. Here we show that male mice chronically exposed to DES exhibit abnormal contractility of the erectile tissue, indicative of ED. The treatment did not affect systemic testosterone production yet significantly increased estrogen receptor α (Esr1) expression in the primary erectile tissue, suggesting EDCs directly impact erectile function. In response, we isolated the erectile tissue from mice and briefly incubated them with the estrogenic-EDCs DES or genistein (a phytoestrogen). These acute-direct exposures similarly caused a significant reduction in erectile tissue contractility, again indicative of ED. Overall, these findings demonstrate a direct link between estrogenic EDCs and erectile dysfunction and show that both chronic and acute estrogenic exposures are likely risk factors for this condition.
Assuntos
Disruptores Endócrinos , Disfunção Erétil , Humanos , Masculino , Camundongos , Animais , Disruptores Endócrinos/toxicidade , Disfunção Erétil/induzido quimicamente , Qualidade de Vida , Fatores de RiscoRESUMO
Preeclampsia is classified as new-onset hypertension coupled with gross endothelial dysfunction. Placental (pro)renin receptor ((P)RR) and plasma soluble (P)RR (s(P)RR) are elevated in patients with preeclampsia. Thus, we aimed to interrogate the role (P)RR may play in the pathogenesis of preeclampsia. Human uterine microvascular endothelial cells (HUtMECs, n = 4) were cultured with either; vehicle (PBS), 25-100 nM recombinant s(P)RR, or 10 ng/ml TNF-a (positive control) for 24 h. Conditioned media and cells were assessed for endothelial dysfunction markers via qPCR, ELISA, and immunoblot. Angiogenic capacity was assessed through tube formation and adhesion assays. Additionally, pregnant rats were injected with an adenovirus overexpressing s(P)RR from mid-pregnancy (day 8.5), until term (n = 6-7 dams/treatment). Maternal and fetal tissues were assessed. HUtMECs treated with recombinant s(P)RR displayed increased expression of endothelial dysfunction makers including vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and endothelin-1 mRNA expression (P = 0.003, P = 0.001, P = 0.009, respectively), along with elevated endothelin-1 protein secretion (P < 0.001) compared with controls. Recombinant s(P)RR impaired angiogenic capacity decreasing the number of branches, total branch length, and mesh area (P < 0.001, P = 0.004, and P = 0.009, respectively), while also increasing vascular adhesion (P = 0.032). +ADV rats exhibited increased systolic (P = 0.001), diastolic (P = 0.010), and mean arterial pressures (P = 0.012), compared with -ADV pregnancies. Renal arteries from +ADV-treated rats had decreased sensitivity to acetylcholine-induced relaxation (P = 0.030), compared with -ADV pregnancies. Our data show that treatment with s(P)RR caused hypertension and growth restriction in vivo and caused marked endothelial dysfunction in vitro. These findings demonstrate the significant adverse actions of s(P)RR on vascular dysfunction that is characteristic of the preeclamptic phenotype.
Assuntos
Células Endoteliais , Pré-Eclâmpsia , Receptores de Superfície Celular , Gravidez , Feminino , Animais , Pré-Eclâmpsia/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/genética , Humanos , Ratos , Células Endoteliais/metabolismo , Ratos Sprague-Dawley , Fenótipo , Células Cultivadas , Receptor de Pró-Renina , Placenta/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Útero/irrigação sanguínea , Útero/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismoRESUMO
Importance: Transplant recipients experience high rates of adverse pregnancy outcomes; however, contemporary estimates of the association between solid organ transplantation and adverse pregnancy outcomes are lacking. Objective: To evaluate the association between solid organ transplantation and adverse pregnancy outcomes and to quantify the incidence of allograft rejection and allograft loss during pregnancy. Data Sources: PubMed/MEDLINE, EMBASE and Scopus databases were searched from January 1, 2000, to June 20, 2024, and reference lists were manually reviewed. Study Selection: Cohort and case-control studies that reported at least 1 adverse pregnancy outcome in pregnant women with solid organ transplantation vs without solid organ transplant or studies that reported allograft outcomes in pregnant women with solid organ transplantation were included following independent dual review of abstracts and full-text articles. Data Extraction and Synthesis: Two investigators abstracted data and independently appraised risk of bias using the Newcastle Ottawa Scale. A random-effects model was used to calculate overall pooled estimates using the DerSimonian-Laird estimator. Reporting followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Main Outcomes and Measures: Primary pregnancy outcomes were preeclampsia, preterm birth (<37 weeks), and low birth weight (<2500 g). Secondary pregnancy outcomes were live birth rate, gestation, very preterm birth (<32 weeks), very low birth weight (<1500 g), and cesarean delivery. Allograft outcomes were allograft loss and rejection during pregnancy. Results: Data from 22 studies and 93â¯565â¯343 pregnancies (4786 pregnancies in solid organ transplant recipients) were included; 14 studies reported adverse pregnancy outcomes, and 13 studies provided data for allograft outcomes. Pregnancies in organ transplant recipients were associated with significantly increased risk of preeclampsia (adjusted odds ratio [aOR], 5.83 [95% CI, 3.45-9.87]; I2 = 77.4%), preterm birth (aOR, 6.65 [95% CI, 4.09-12.83]; I2 = 81.8%), and low birth weight (aOR, 6.51 [95% CI, 2.85-14.88]; I2 = 90.6%). The incidence of acute allograft rejection was 2.39% (95% CI, 1.20%-3.96%; I2 = 68.5%), and the incidence of allograft loss during pregnancy was 1.55% (95% CI, 0.05%-4.44%; I2 = 69.2%). Conclusions and Relevance: In this systematic review and meta-analysis, pregnancies in recipients of a solid organ transplant were associated with a 4 to 6 times increased risk of preeclampsia, preterm birth, and low birth weight during pregnancy. There was a low overall risk of graft rejection or loss during pregnancy.