RESUMEN
Regulatory T (Treg) cells are essential for immune tolerance of embryo implantation, and insufficient Treg cells are implicated in early pregnancy loss. An abortion-prone mouse model was used to evaluate the utility of IL-2 complexed with JES6-1 anti-IL-2 antibody (IL-2/JES6-1) to boost uterine Treg cells and improve reproductive success. IL-2/JES6-1, but not IL-2/IgG control, administered in the periconception phase to CBA/J females mated with DBA/2 males elicited a greater than twofold increase in the proportion of CD4+ T cells expressing forkhead box P3 (FOXP3), and an increase in the ratio of FOXP3+ Treg cells/FOXP3- T conventional cells, in the uterus and its draining lymph nodes at embryo implantation that was sustained into midgestation. An attenuated phenotype was evident in both thymic-derived and peripheral Treg cells with elevated cytotoxic T-lymphocyte antigen-4, CD25, and FOXP3, indicating improved suppressive function, as well as increased proliferative marker Ki-67. IL-2/JES6-1 treatment reduced fetal loss from 31% to 10%, but this was accompanied by a 6% reduction in late gestation fetal weight, despite comparable placental size and architecture. Similar effects of IL-2/JES6-1 on Treg cells and fetal growth were seen in CBA/J females with healthy pregnancies sired by BALB/c males. These findings show that expanding the uterine Treg cell pool through targeting IL-2 signaling is a strategy worthy of further investigation for mitigating immune-mediated fetal loss.
RESUMEN
Maternal mortality rates are at an all-time high across the world and are set to increase in subsequent years. Cardiovascular disease is the leading cause of death during pregnancy and postpartum, especially in the United States. Therefore, understanding the physiological changes in the cardiovascular system during normal pregnancy is necessary to understand disease-related pathology. Significant systemic and cardiovascular physiological changes occur during pregnancy that are essential for supporting the maternal-fetal dyad. The physiological impact of pregnancy on the cardiovascular system has been examined in both experimental animal models and in humans. However, there is a continued need in this field of study to provide increased rigor and reproducibility. Therefore, these guidelines aim to provide information regarding best practices and recommendations to accurately and rigorously measure cardiovascular physiology during normal and cardiovascular disease-complicated pregnancies in human and animal models.
Asunto(s)
Fenómenos Fisiológicos Cardiovasculares , Periodo Posparto , Embarazo , Humanos , Femenino , Animales , Complicaciones Cardiovasculares del Embarazo/fisiopatología , Sistema Cardiovascular/fisiopatología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/diagnósticoRESUMEN
Animal models are needed to develop interventions to prevent or treat intrauterine growth restriction (IUGR). Foetal growth rates and effects of in utero exposures differ between sexes, but little is known about sex-specific effects of increasing litter size. We established a murine IUGR model using pregnancies generated by multiple embryo transfers, and evaluated sex-specific responses to increasing litter size. CBAF1 embryos were collected at gestation day 0.5 (GD0.5) and 6, 8, 10 or 12 embryos were transferred into each uterine horn of pseudopregnant female CD1 mice (n = 32). Foetal and placental outcomes were measured at GD18.5. In the main experiment, foetuses were genotyped (Sry) for analysis of sex-specific outcomes. The number of implantation sites (P = 0.033) and litter size (number of foetuses, P = 0.008) correlated positively with the number of embryos transferred, while placental weight correlated negatively with litter size (both P < 0.01). The relationship between viable litter size and foetal weight differed between sexes (interaction P = 0.002), such that foetal weights of males (P = 0.002), but not females (P = 0.233), correlated negatively with litter size. Placental weight decreased with increasing litter size (P < 0.001) and was lower in females than males (P = 0.020). Our results suggest that male foetuses grow as fast as permitted by nutrient supply, whereas the female maintains placental reserve capacity. This strategy reflecting sex-specific gene expression is likely to place the male foetus at greater risk of death in the event of a 'second hit'.
Asunto(s)
Retardo del Crecimiento Fetal , Placenta , Animales , Modelos Animales de Enfermedad , Transferencia de Embrión , Femenino , Peso Fetal , Tamaño de la Camada , Masculino , Ratones , EmbarazoRESUMEN
KEY POINTS: Advanced maternal age increases the risk of pregnancy complications such as fetal growth restriction, hypertension and premature birth. Offspring born from compromised pregnancies are at increased risk of cardiovascular disease as adults. However, the effect of advanced maternal age on later-onset disease in offspring has not been investigated. In adulthood, male but not female offspring born to dams of advanced maternal age showed impaired recovery from cardiac ischaemia/reperfusion injury. Endothelium-dependent relaxation was also impaired in male but not female offspring born from aged dams. Oxidative stress may play a role in the developmental programming of cardiovascular disease in this model. Given the increasing trend toward delayed parenthood, these findings have significant population and health care implications and warrant further investigation. ABSTRACT: Exposure to prenatal stressors, including hypoxia, micro- and macronutrient deficiency, and maternal stress, increases the risk of cardiovascular disease in adulthood. It is unclear whether being born from a mother of advanced maternal age (≥35 years old) may also constitute a prenatal stress with cardiovascular consequences in adulthood. We previously demonstrated growth restriction in fetuses from a rat model of advanced maternal age, suggesting exposure to a compromised in utero environment. Thus, we hypothesized that male and female offspring from aged dams would exhibit impaired cardiovascular function as adults. In 4-month-old offspring, we observed impaired endothelium-dependent relaxation in male (P < 0.05) but not female offspring born from aged dams. The anti-oxidant polyethylene glycol superoxide dismutase improved relaxation only in arteries from male offspring of aged dams (ΔEmax : young dam -1.63 ± 0.80 vs. aged dam 11.75 ± 4.23, P < 0.05). Furthermore, endothelium-derived hyperpolarization-dependent relaxation was reduced in male but not female offspring of aged dams (P < 0.05). Interestingly, there was a significant increase in nitric oxide contribution to relaxation in females born from aged dams (ΔEmax : young dam -24.8 ± 12.1 vs. aged dam -68.7 ± 7.7, P < 0.05), which was not observed in males. Recovery of cardiac function following an ischaemia-reperfusion insult in male offspring born from aged dams was reduced by â¼57% (P < 0.001), an effect that was not evident in female offspring. These data indicate that offspring born from aged dams have an altered cardiovascular risk profile that is sex-specific. Given the increasing trend toward delaying pregnancy, these findings may have significant population and health care implications and warrant further investigation.
Asunto(s)
Enfermedades Cardiovasculares/fisiopatología , Endotelio Vascular/fisiología , Edad Materna , Envejecimiento/fisiología , Animales , Presión Sanguínea , Femenino , Corazón/fisiología , Masculino , Estrés Oxidativo , Embarazo , RatasRESUMEN
Pregnancy at an advanced maternal age has an increased risk of complications for both the mothers and their offspring. We have previously shown that advanced maternal age in a rat model leads to poor fetal outcomes, maternal vascular dysfunction, and hypertension, concordant with findings in humans. Moreover, offspring from aged dams had sex-specific cardiovascular dysfunction in young adulthood. However, the detrimental impact of aging on the cardiovascular system of the offspring in this model is unknown. We hypothesized that offspring born to aged dams (9.5-10 mo old) would have impaired cardiovascular function at 12 mo of age. Echocardiographic data revealed signs of mild left ventricular diastolic dysfunction in only male offspring from aged dams [isovolumetric relaxation time: 34.27 ± 2.04 in the young dam group vs. 27.61 ± 0.99 ms in the aged dam group, P < 0.01; mitral annular velocity ratio ( E'/ A'): 1.08 ± 0.04 in the young dam group vs. 0.96 ± 0.02 in the aged dam group, P < 0.05]. We have previously shown that in young adulthood (4 mo of age), male, but not female, offspring born to aged dams had impaired recovery from ischemia-reperfusion injury. Aging did not alter the susceptibility of female offspring to ischemia-reperfusion injury. Interestingly, wire myography data revealed that male offspring from aged dams had enhanced vascular sensitivity to methacholine (negative log of EC50: 7.4 ± 0.08 in young dams vs. 7.9 ± 0.11 in aged dams, P = 0.007) due, in part, to increased prostaglandin-mediated vasodilation. Despite intact endothelium-dependent relaxation, female offspring from aged dams had elevated systolic blood pressure (125.3 ± 4.2 mmHg in young dams vs. 144.0 ± 6.9 mmHg in aged dams, P = 0.03). These data highlight sex-specific mechanisms underlying cardiovascular programming in offspring born to dams of advanced age. NEW & NOTEWORTHY Our study demonstrated that adult male and female offspring (12 mo old) born to aged dams had impaired cardiac diastolic function and increased blood pressure, respectively, signifying sex-specific differential cardiovascular effects of advanced maternal age.
Asunto(s)
Edad Materna , Daño por Reperfusión Miocárdica/fisiopatología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Disfunción Ventricular/fisiopatología , Animales , Presión Sanguínea , Femenino , Masculino , Daño por Reperfusión Miocárdica/etiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Ratas , Ratas Sprague-Dawley , Factores Sexuales , Vasodilatación , Disfunción Ventricular/etiologíaRESUMEN
Pregnancy is a unique condition, and the vascular processes that are required for this undertaking are both complex and extensive. In this review, we discuss the vascular adaptations which occur in the maternal uterine arterial bed to maintain blood supply to the fetal-placental unit. In complicated pregnancies, inadequate remodeling of the uterine arteries, hormonal imbalances, and pre-existing conditions such as obesity, hypertension, diabetes etc. may lead to maladaptations of the uterine vasculature that includes increased vasoconstriction and endothelial dysfunction. Ultimately, uterine artery dysfunction results in increased vascular resistance impeding blood flow to the fetal-placental unit and limiting fetal growth and development. A strong association exists between poor fetal development in utero and later life health issues, which can include obesity, poor neurological development, and enhanced susceptibility to cardiovascular disease. Therefore, the detrimental outcomes of a complicated pregnancy are far-reaching and significantly impact the health of the population as a whole. Many treatment options to improve maternal uterine artery function and ameliorate the impact on the fetus are being considered. A particular difficulty in treating complicated pregnancies is the presence of not 1 but (at least) 2 patients. Novel approaches are required to successfully improve pregnancy outcomes and minimize the impact on later life health.
Asunto(s)
Hemodinámica , Circulación Placentaria , Complicaciones del Embarazo/fisiopatología , Arteria Uterina/fisiopatología , Adaptación Fisiológica , Animales , Femenino , Humanos , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/metabolismo , Efectos Tardíos de la Exposición Prenatal , Medición de Riesgo , Factores de Riesgo , Arteria Uterina/metabolismoRESUMEN
Paternal characteristics and exposures influence physiology and disease risks in progeny, but the mechanisms are mostly unknown. Seminal fluid, which affects female reproductive tract gene expression as well as sperm survival and integrity, provides one potential pathway. We evaluated in mice the consequences for offspring of ablating the plasma fraction of seminal fluid by surgical excision of the seminal vesicle gland. Conception was substantially impaired and, when pregnancy did occur, placental hypertrophy was evident in late gestation. After birth, the growth trajectory and metabolic parameters of progeny were altered, most profoundly in males, which exhibited obesity, distorted metabolic hormones, reduced glucose tolerance, and hypertension. Altered offspring phenotype was partly attributable to sperm damage and partly to an effect of seminal fluid deficiency on the female tract, because increased adiposity was also evident in adult male progeny when normal two-cell embryos were transferred to females mated with seminal vesicle-excised males. Moreover, embryos developed in female tracts not exposed to seminal plasma were abnormal from the early cleavage stages, but culture in vitro partly alleviated this. Absence of seminal plasma was accompanied by down-regulation of the embryotrophic factors Lif, Csf2, Il6, and Egf and up-regulation of the apoptosis-inducing factor Trail in the oviduct. These findings show that paternal seminal fluid composition affects the growth and health of male offspring, and reveal that its impact on the periconception environment involves not only sperm protection but also indirect effects on preimplantation embryos via oviduct expression of embryotrophic cytokines.
Asunto(s)
Genitales Femeninos/fisiología , Semen , Animales , Presión Sanguínea , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos CBA , FenotipoRESUMEN
Macrophages are abundant in the uterine stroma and are intimately juxtaposed with other cell lineages comprising the uterine epithelial and stromal compartments. We postulated that macrophages may participate in mediating or amplifying the effects of ovarian steroid hormones to facilitate the uterine remodeling that is a characteristic feature of every estrus cycle and is essential for pregnancy. Using the Cd11b-Dtr transgenic mouse model with an ovariectomy and hormone replacement strategy, we depleted macrophages to determine their role in hormone-driven proliferation of uterine epithelial and stromal cells and uterine vascular development. Following diphtheria toxin (DT) administration, approximately 85% of EMR1-positive (EMR1âº) macrophages, as well as 70% of CD11C⺠dendritic cells, were depleted from Cd11b-Dtr mice. There was no change in bromodeoxyuridine incorporation into epithelial cells induced to proliferate by administration of 17beta-estradiol (E2) to ovariectomized mice or into stromal cells induced to proliferate in response to E2 and progesterone (P4), and the resulting sizes and structures of the luminal epithelial and stromal cell compartments were not altered compared with those of leukocyte replete controls. Depletion of CD11B⺠myeloid cells failed to alter the density or pattern of distribution of uterine blood vessels, as identified by staining PECAM1-positive endothelial cells in the uterine stroma of E2- or E2 combined with P4 (E2P4)-treated ovariectomized mice. These experiments support the interpretation that macrophages are dispensable to regulation of proliferative events induced by steroid hormones in the cycling and early pregnant mouse uterus to establish the epithelial, stromal, and vascular architecture which is critical for normal reproductive competence.
Asunto(s)
Endometrio/inmunología , Estradiol/metabolismo , Ciclo Estral , Macrófagos/inmunología , Progesterona/metabolismo , Útero/inmunología , Remodelación Vascular , Animales , Biomarcadores/metabolismo , Proliferación Celular , Toxina Diftérica , Endometrio/irrigación sanguínea , Endometrio/citología , Endometrio/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Femenino , Terapia de Reemplazo de Hormonas , Inmunohistoquímica , Terapia de Inmunosupresión , Macrófagos/citología , Macrófagos/metabolismo , Ratones Transgénicos , Ovariectomía , Organismos Libres de Patógenos Específicos , Útero/irrigación sanguínea , Útero/citología , Útero/metabolismoRESUMEN
Progesterone (P4) is essential for embryo implantation, but the extent to which the pro-gestational effects of P4 depend on the maternal immune compartment is unknown. Here, we investigate whether regulatory T cells (Treg cells) act to mediate luteal phase P4 effects on uterine receptivity in mice. P4 antagonist RU486 administered to mice on days 0.5 and 2.5 postcoitum to model luteal phase P4 deficiency caused fewer CD4+Foxp3+ Treg cells and impaired Treg functional competence, along with dysfunctional uterine vascular remodeling and perturbed placental development in midgestation. These effects were linked with fetal loss and fetal growth restriction, accompanied by a Th1/CD8-skewed T cell profile. Adoptive transfer at implantation of Treg cells - but not conventional T cells - alleviated fetal loss and fetal growth restriction by mitigating adverse effects of reduced P4 signaling on uterine blood vessel remodeling and placental structure and by restoring maternal T cell imbalance. These findings demonstrate an essential role for Treg cells in mediating P4 effects at implantation and indicate that Treg cells are a sensitive and critical effector mechanism through which P4 drives uterine receptivity to support robust placental development and fetal growth.
Asunto(s)
Progesterona , Linfocitos T Reguladores , Humanos , Embarazo , Femenino , Animales , Ratones , Progesterona/farmacología , Placenta , Retardo del Crecimiento Fetal , Implantación del Embrión/fisiología , Desarrollo FetalRESUMEN
Female cancer survivors are significantly more likely to experience infertility than the general population. It is well established that chemotherapy and radiotherapy can damage the ovary and compromise fertility, yet the ability of cancer treatments to induce uterine damage, and the underlying mechanisms, have been understudied. Here, we show that in mice total-body γ-irradiation (TBI) induced extensive DNA damage and apoptosis in uterine cells. We then transferred healthy donor embryos into ovariectomized adolescent female mice that were previously exposed to TBI to study the impacts of radiotherapy on the uterus independent from effects to ovarian endocrine function. Following TBI, embryo attachment and implantation were unaffected, but fetal resorption was evident at midgestation in 100% of dams, suggesting failed placental development. Consistent with this hypothesis, TBI impaired the decidual response in mice and primary human endometrial stromal cells. TBI also caused uterine artery endothelial dysfunction, likely preventing adequate blood vessel remodeling in early pregnancy. Notably, when pro-apoptotic protein Puma-deficient (Puma-/-) mice were exposed to TBI, apoptosis within the uterus was prevented, and decidualization, vascular function, and pregnancy were restored, identifying PUMA-mediated apoptosis as a key mechanism. Collectively, these data show that TBI damages the uterus and compromises pregnancy success, suggesting that optimal fertility preservation during radiotherapy may require protection of both the ovaries and uterus. In this regard, inhibition of PUMA may represent a potential fertility preservation strategy.
Asunto(s)
Proteínas Reguladoras de la Apoptosis , Placenta , Embarazo , Femenino , Humanos , Ratones , Animales , Adolescente , Proteínas Reguladoras de la Apoptosis/metabolismo , Útero/metabolismo , Implantación del Embrión/fisiología , PlacentaciónRESUMEN
Immune cells are essential for endometrial receptivity to embryo implantation and early placental development. They exert tissue-remodeling and immune regulatory roles-acting to promote epithelial attachment competence, regulate the differentiation of decidual cells, remodel the uterine vasculature, control and resolve inflammatory activation, and suppress destructive immunity to paternally inherited alloantigens. From a biological perspective, the endometrial immune response exerts a form of "quality control"-it promotes implantation success when conditions are favorable but constrains receptivity when physiological circumstances are not ideal. Women with recurrent implantation failure and recurrent miscarriage may exhibit altered numbers or disturbed function of certain uterine immune cell populations-most notably uterine natural killer cells and regulatory T cells. Preclinical and animal studies indicate that deficiencies or aberrant activation states in these cells can be causal in the pathophysiological mechanisms of infertility. Immune cells are, therefore, targets for diagnostic evaluation and therapeutic intervention. However, current diagnostic tests are overly simplistic and have limited clinical utility. To be more informative, they need to account for the full complexity and reflect the range of perturbations that can occur in uterine immune cell phenotypes and networks. Moreover, safe and effective interventions to modulate these cells are in their infancy, and personalized approaches matched to specific diagnostic criteria will be needed. Here we summarize current biological understanding and identify knowledge gaps to be resolved before the promise of therapies to target the uterine immune response can be fully realized.
Asunto(s)
Aborto Habitual , Placenta , Aborto Habitual/diagnóstico , Animales , Implantación del Embrión/fisiología , Endometrio/fisiología , Femenino , Humanos , Embarazo , ÚteroRESUMEN
Macrophages accumulate within stromal tissue subjacent to the luminal epithelium in the mouse uterus during early pregnancy after seminal fluid exposure at coitus. To investigate their role in regulating epithelial cell expression of fucosylated structures required for embryo attachment and implantation, fucosyltransferase enzymes Fut1, Fut2 (Enzyme Commission number [EC] 2.4.1.69), and Fut4 (EC 2.4.1.214) and Muc1 and Muc4 mRNAs were quantified by quantitative real-time PCR in uterine epithelial cells after laser capture microdissection in situ or after epithelial cell coculture with macrophages or macrophage-secreted factors. When uterine macrophage recruitment was impaired by mating with seminal plasma-deficient males, epithelial cell Fut2 expression on Day 3.5 postcoitus (pc) was reduced compared to intact-mated controls. Epithelial cell Fut2 was upregulated in vitro by coculture with macrophages or macrophage-conditioned medium (MCM). Macrophage-derived cytokines LIF, IL1B, and IL12 replicated the effect of MCM on Fut2 mRNA expression, and MCM-stimulated expression was inhibited by anti-LIF and anti-IL1B neutralizing antibodies. The effects of acute macrophage depletion on fucosylated structures detected with lectins Ulex europaeus 1 (UEA-1) and Lotus tetragonolobus purpureas (LTP), or LewisX immunoreactivity, were quantified in vivo in Cd11b-dtr transgenic mice. Depletion of macrophages caused a 30% reduction in luminal epithelial UEA-1 staining and a 67% reduction in LewisX staining in uterine tissues of mice hormonally treated to mimic early pregnancy. Together, these data demonstrate that uterine epithelial Fut2 mRNA expression and terminal fucosylation of embryo attachment ligands is regulated in preparation for implantation by factors including LIF and IL1B secreted from macrophages recruited during the inflammatory response to insemination.
Asunto(s)
Células Epiteliales/enzimología , Fucosiltransferasas/metabolismo , Regulación Enzimológica de la Expresión Génica/fisiología , Interleucina-1beta/metabolismo , Factor Inhibidor de Leucemia/metabolismo , Macrófagos/metabolismo , Animales , Endotelio/citología , Femenino , Fucosiltransferasas/genética , Interleucina-1beta/genética , Factor Inhibidor de Leucemia/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Útero/citología , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
Advanced imaging techniques are enhancing research capacity focussed on the developmental origins of adult health and disease (DOHaD) hypothesis, and consequently increasing awareness of future health risks across various subareas of DOHaD research themes. Understanding how these advanced imaging techniques in animal models and human population studies can be both additively and synergistically used alongside traditional techniques in DOHaD-focussed laboratories is therefore of great interest. Global experts in advanced imaging techniques congregated at the advanced imaging workshop at the 2019 DOHaD World Congress in Melbourne, Australia. This review summarizes the presentations of new imaging modalities and novel applications to DOHaD research and discussions had by DOHaD researchers that are currently utilizing advanced imaging techniques including MRI, hyperpolarized MRI, ultrasound, and synchrotron-based techniques to aid their DOHaD research focus.
Asunto(s)
Investigación Biomédica/tendencias , Diagnóstico por Imagen/métodos , Enfermedades Fetales/diagnóstico , Feto/patología , Femenino , Enfermedades Fetales/diagnóstico por imagen , Feto/diagnóstico por imagen , Humanos , Embarazo , Sociedades CientíficasRESUMEN
Preeclampsia is a common pregnancy complication, affecting 2% to 8% of pregnancies worldwide, and is an important cause of both maternal and fetal morbidity and mortality. Importantly, although aspirin and calcium are able to prevent preeclampsia in some women, there is no cure apart from delivery of the placenta and fetus, often necessitating iatrogenic preterm birth. Preclinical models of preeclampsia are widely used to investigate the causes and consequences of preeclampsia and to evaluate safety and efficacy of potential preventative and therapeutic interventions. In this review, we provide a summary of the published preclinical models of preeclampsia that meet human diagnostic criteria, including the development of maternal hypertension, together with new-onset proteinuria, maternal organ dysfunction, and uteroplacental dysfunction. We then discuss evidence from preclinical models for multiple causal factors of preeclampsia, including those implicated in early-onset and late-onset preeclampsia. Next, we discuss the impact of exposure to a preeclampsia-like environment for later maternal and progeny health. The presence of long-term impairment, particularly cardiovascular outcomes, in mothers and progeny after an experimentally induced preeclampsia-like pregnancy, implies that later onset or reduced severity of preeclampsia will improve later maternal and progeny health. Finally, we summarize published intervention studies in preclinical models and identify gaps in knowledge that we consider should be targets for future research.
Asunto(s)
Preeclampsia , Animales , Modelos Animales de Enfermedad , Femenino , Preeclampsia/etiología , Preeclampsia/fisiopatología , Preeclampsia/terapia , EmbarazoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
The immune-regulatory microRNA miR-155 is reduced in recurrent miscarriage, suggesting that miR-155 contributes to immune tolerance in pregnancy. Here we show miR-155 is induced in the uterine mucosa and draining lymph nodes (dLN) during the female immune response to male seminal fluid alloantigens. Mice with null mutation in miR-155 (miR-155-/-) exhibited a reduced CD4+ T cell response after mating, with a disproportionate loss of CD25+FOXP3+ Treg cells. miR-155 deficiency impaired expansion of both peripheral and thymic Treg cells, distinguished by neuropilin-1 (NRP1), and fewer Treg cells expressed Ki67 proliferation marker and suppressive function marker CTLA4. Altered Treg phenotype distribution in miR-155-/- mice was confirmed by t-distributed neighbor embedding (tSNE) analysis. Fewer dendritic cells (DCs) and macrophages trafficked to the dLN of miR-155-/- mice, associated with lower CCR7 on DCs, and reduced uterine Ccl19 expression, implicating compromised antigen presentation in the stunted Treg cell response. miR-155-/- mice exhibited elevated susceptibility to inflammation-induced fetal loss and fetal growth restriction compared with miR-155+/+ controls, but outcomes were restored by transfer of wild-type Tregs. Thus miR-155 is a key regulator of immune adaptation to pregnancy and is necessary for sufficient Tregs to achieve robust pregnancy tolerance and protect against fetal loss.
Asunto(s)
Tolerancia Inmunológica/genética , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , MicroARNs/genética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Aborto Espontáneo/etiología , Aborto Espontáneo/metabolismo , Animales , Biomarcadores , Citocinas/sangre , Citocinas/metabolismo , Femenino , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Edad Gestacional , Inmunohistoquímica , Inmunomodulación/genética , Inmunofenotipificación , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ratones , Embarazo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Útero/inmunología , Útero/metabolismoRESUMEN
Preeclampsia (PE) is now recognised as a cardiovascular risk factor for women. Emerging evidence suggests that children exposed to PE in utero may also be at increased risk of cardiovascular disease (CVD) in later life. Individuals exposed to PE in utero have higher systolic and diastolic blood pressure and higher body mass index (BMI) compared to those not exposed to PE in utero. The aim of this review is to discuss the potential mechanisms driving the relationship between PE and offspring CVD. Exposure to an adverse intrauterine environment as a consequence of the pathophysiological changes that occur during a pregnancy complicated by PE is proposed as one mechanism that programs the fetus for future CVD risk. Consistent with this hypothesis, animal models of PE where progeny have been studied demonstrate causality for programming of offspring cardiovascular health by the preeclamptic environment. Shared alleles between mother and offspring, and shared lifestyle factors between mother and offspring provide alternate pathways explaining associations between PE and offspring CVD risk. In addition, adverse lifestyle habits can also act as second hits for those programmed for increased CVD risk. PE and CVD are both multifactorial diseases and, hence, identifying the relative contribution of PE to offspring risk for CVD is a very complex task. However, considering the emerging strong association between PE and CVD, those exposed to PE in utero may benefit from targeted primary CVD preventive strategies.
Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Preeclampsia/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Animales , Presión Sanguínea/fisiología , Índice de Masa Corporal , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Modelos Animales de Enfermedad , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/prevención & control , Medición de Riesgo/estadística & datos numéricosRESUMEN
Advanced maternal age is associated with an increased risk of pregnancy complications. It programmes sex-specific cardiovascular dysfunction in rat offspring, however the intrauterine mechanisms involved remain unknown. This study in the rat assessed the impact of advanced maternal age on placental phenotype in relation to the growth of female and male fetuses. We show that relative to young (3-4 months) dams, advanced maternal age (9.5-10 months) compromises growth of both female and male fetuses but affects the placental phenotype sex-specifically. In placentas from aged versus young dams, the size of the placental transport and endocrine zones were increased and expression of Igf2 (+41%) and placental lactogen (Prl3b1: +59%) genes were upregulated in female, but not male fetuses. Placental abundance of IGF2 protein also decreased in the placenta of males only (-95%). Moreover, in placentas from aged versus young dams, glucocorticoid metabolism (11ß-hsd2: +63% and 11ß-hsd1: -33%) was higher in females, but lower in males (11ß-hsd2: -50% and 11ß-hsd1: unaltered). There was however, no change in the placental abundance of 11ß-HSD2 protein in aged versus young dams regardless of fetal sex. Levels of oxidative stress in the placenta were increased in female and male fetuses (+57% and +90%, respectively) and apoptosis increased specifically in the placenta of males from aged rat dams (+700%). Thus, advanced maternal age alters placental phenotype in a sex-specific fashion. These sexually-divergent changes may play a role in determining health outcomes of female and male offspring of aged mothers.
Asunto(s)
Retardo del Crecimiento Fetal/etiología , Edad Materna , Placenta/anatomía & histología , Animales , Femenino , Desarrollo Fetal , Retardo del Crecimiento Fetal/patología , Masculino , Fenotipo , Embarazo , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
INTRODUCTION: Proper placental function is essential for optimal fetal growth in utero. Placental transfer of nutrients to the fetus can be measured using radiolabelled tracers, but non-radioactive methods have potential advantages. This study aimed to develop a fluorescence-based method to measure placental glucose transport in mice. METHODS: Time course and localisation of the IRDye 800CW 2-deoxyglucose were recorded (Lumina IVIS Live Imaging System) following tail vein injection into anaesthetised late pregnant mice. Fluorescent signals in placental and fetal tissues were assessed after injecting conscious dams with 10â¯nmol IRDye 800CW 2-deoxyglucose (3, 30, 60, 120â¯min) or vehicle. Specificity of dye uptake was determined by comparing uptake of IRDye 800CW conjugated to 2-deoxyglucose or carboxylate, at 2 and 24â¯h. Finally, we assessed relationships of fetal size and umbilical blood flow velocities with relative dye uptake. RESULTS: In late pregnant mice, uterine fluorescent signal localised rapidly over placentas and remained consistent for >1â¯h. Signal intensity in whole and homogenised tissues increased in fetuses and decreased in placentas after 3â¯min and stabilised by 30â¯min post-injection. Relative fetal dye uptake at 2 and 24â¯h was greater in littermates with the highest compared to lowest placental efficiency; signals were similar for 2-deoxyglucose- or carboxylate-conjugated dyes. Relative fetal dye uptake correlated positively with fetal weight and placental efficiency and negatively with umbilical artery resistance indices. CONCLUSIONS: Fetal uptake of IRDye 800CW correlates with markers of placental blood flow and fetal growth, but does not specifically measure placental glucose transport.
Asunto(s)
Colorantes Fluorescentes , Glucosa/análisis , Placenta/metabolismo , Animales , Femenino , Feto/irrigación sanguínea , Glucosa/metabolismo , Ratones Endogámicos C57BL , EmbarazoRESUMEN
Inflammation is a central feature and is implicated as a causal factor in preeclampsia and other hypertensive disorders of pregnancy. Inflammatory mediators and leukocytes, which are elevated in peripheral blood and gestational tissues, contribute to the uterine vascular anomalies and compromised placental function that characterize particularly the severe, early onset form of disease. Regulatory T (Treg) cells are central mediators of pregnancy tolerance and direct other immune cells to counteract inflammation and promote robust placentation. Treg cells are commonly perturbed in preeclampsia, and there is evidence Treg cell insufficiency predates onset of symptoms. A causal role is implied by mouse studies showing sufficient numbers of functionally competent Treg cells must be present in the uterus from conception, to support maternal vascular adaptation and prevent later placental inflammatory pathology. Treg cells may therefore provide a tractable target for both preventative strategies and treatment interventions in preeclampsia. Steps to boost Treg cell activity require investigation and could be incorporated into pregnancy planning and preconception care. Pharmacological interventions developed to target Treg cells in autoimmune conditions warrant consideration for evaluation, utilizing rigorous clinical trial methodology, and ensuring safety is paramount. Emerging cell therapy tools involving in vitro Treg cell generation and/or expansion may in time become relevant. The success of preventative and therapeutic approaches will depend on resolving several challenges including developing informative diagnostic tests for Treg cell activity applicable before conception or during early pregnancy, selection of relevant patient subgroups, and identification of appropriate windows of gestation for intervention.