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Orientadores: Carlos A. M. Guerreiro, Iscia T. Lopes-Cendes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T14:30:31Z (GMT). No. of bitstreams: 1 Costa_AlbertoLuizCunhada_D.pdf: 10395581 bytes, checksum: a6d86ff240a4e83b2dc8cdef41ca4db7 (MD5) Previous issue date: 2007 / Resumo: A maioria das gestações em mulheres com epilepsia não apresenta complicações, porém a persistência de crises e efeitos das drogas antiepilépticas (DAE) podem afetar o feto causando retardo do crescimento intra-uterino, dismorfismos, atraso do desenvolvimento neuro-psicomotor e malformações fetais, com aumento no risco estimado em 2 a 3 vezes em fetos expostos intrautero. Os objetivos foram identificar a ocorrência de malformações fetais em filhos de mães com epilepsia; determinar a ocorrência de atraso de desenvolvimento intra-uterino; investigar o crescimento e desenvolvimento de filhos de mães com epilepsia e descrever os achados e complicações materno-fetais nos grupos de gestantes com epilepsia. Entre maio de 2003 a maio de 2007, foram avaliadas 67 gestantes com epilepsia (GE) com um total de 69 gestações, com idades entre 17 e 37 anos, média 26,9 anos, e 66 gestantes não epilépticas (grupo controle - GC) com um total de 68 gestações, com idades entre 15 e 44 anos, média 26,9 anos, nos ambulatórios de Epilepsia e Genética Clínica do HC ¿ Unicamp. Duas pacientes do GE abandonaram o estudo, sendo recuperados os dados de uma paciente. Quarenta gestantes do GC abandonaram o seguimento. De 42 gestações, em 21 os dados foram recuperados para informações do parto e malformações fetais. Em vinte e uma não foi possível a recuperação. O seguimento longitudinal foi composto por 52 gestações de mulheres com epilepsia e vinte e seis gestantes não epilépticas. Quarenta e cinco pacientes estavam sob monoterapia, 13 com duas DAE e duas com três DAE. Carbamazepina foi usada por 38 gestantes, 26 em monoterapia e 12 em politerapia. Fenobarbital foi a segunda DAE mais usada, sob monoterapia em 07 e politerapia em 05. Três pacientes foram mantidas sem DAE. Todas as pacientes foram atendidas mensalmente pelo mesmo neurologista durante a gestação e puerpério conforme protocolo pré-estabelecido. Estudo antropométrico e neurológico dos neonatos foram realizados por geneticista no nascimento, aos 06 meses, 01 ano, 02, 05 e 07 anos de idade. Filhos de mães com epilepsia (FME) apresentaram menor peso ao nascer, porém índice de Apgar no 1º e 5º minutos não diferiu entre GE e GC. Malformações fetais maiores foram observadas em 16,39% das pacientes do GE (defeitos urogenitais ¿ 2, fenda labial + palatina ¿ 1, defeitos gastrointestinais ¿ 1, anormalidades esqueléticas ¿ 1, hérnias ¿ 2 e deficiência auditiva profunda ¿ 3) e 3,92% no GC (malformações cardiovasculares ¿ 2). Entre os sinais dismórficos estudados, anomalias de orelhas (28,85%), hipertelorismo (62,96%) e diminuição do perímetro cefálico (14,29%) foram mais freqüentes em FME expostos a crises parciais complexas e fenobarbital. Três mulheres do GE apresentaram partos com complicações: Uma criança nasceu com encefalopatia hipóxico-isquêmica, uma apresentou pneumotórax e um parto evoluiu com placenta prévia. Abortos (1), óbitos perinatais (1) e infantis (2) ocorreram apenas em FME. Concluímos que malformações fetais maiores são mais freqüentes em FME comparados com controles. Crises parciais complexas e fenobarbital estão associados com anomalias de orelhas, hipertelorismo e redução do perímetro craniano no seguimento longitudinal. Abortos, óbitos perinatais e infantis ocorreram apenas em FME / Abstract: Rationale: The majority of women with epilepsy do not experience significant changes during pregnancy; however the persistence of seizures and the effect of antiepileptic drugs (AED) may affect the fetus. These effects include lower intrauterine growth, dysmorphisms, fetal malformation and neuropsicomotor developmental delay. Most studies report that the risk of fetal malformation is two to three times higher in fetus exposed to AED. Objectives: The goals of our study were: to identify the occurrence of fetal malformation in children of woman with epilepsy (WWE); to determine the occurrence of intrauterine developmental delay; to investigate the growth and development of these children; to describe labor complications; and to assess birth and child outcome. Methods: From May 2003 to May 2007 we evaluated 67 WWE in 69 gestations, ages ranging from 17 to 37 years, average 26.9 years. Those patients were compared with 66 non-epileptic pregnant women (control group) with 68 gestations, ages ranging from 15 to 44 years, average 26.9 years. Patients were referred from the Epilepsy Unit and Medical Genetics section of Hospital das Clínicas ¿ Unicamp. Results: Two WWE abandoned the study, although the data of one of them were recover. Forty women of the non-epileptic group quitted the study but we were able to recovered the data of 21 of these women reporting on the delivery and fetal malformations. Twenty-one women had their information lost. Follow-up was obtained in 52 WWE and 26 control women. Forty-five women were on one AED, 13 were on two AED and two were on three. Carbamazepine was used by 38 pregnant women, 26 were in monotherapy and 12 were in polytheraphy. Phenobarbital was the second most used AED, seven in monotherapy and five in polytheraphy. Three patients were on no medication. All patients were seen by the same neurologist, monthly during pregnancy and the post gestation period. In addition, anthropometric and neurological evaluation were performed by a geneticist at birth period, six month, 1, 2, 5 and 7 years of age. Three children of WWE presented complications: hypoxic ischemic encephalopathy (1), abruptio placentae (1) and pneumothorax (1). Low birth weight was identified in children of WWE. There was no difference in the Apgar scores in the first and fifth minutes, and head circunference in the two groups. Ten (16.39%) children from WWE (urogenital anomalies ¿ 2, cleft lip+cleft palate ¿ 1, gastrointestinal defects ¿ 1, skeletal defects ¿ 1, hernia ¿ 2, congenital deafness ¿ 3) and two (3.92%) of the control group (cardiac defects ¿ 2) showed major fetal malformations. Dysmorphic signs such as ear anomalies (28.85%), hypertelorism (62.96%), and small head circumference, were more frequent in children of epileptic mother, particularly associated with use of phenobarbital and complex partial seizures. Conclusions: We conclude that major fetal malformations were more frequent in children of WWE (16.39%) compared to controls (3.92%). Children of mothers with complex partial seizures, using phenobarbital presented more ear anomalies (28.85%), increased intercantal distance (62.96%) and smaller head circunference (14.29%) in longitudinal follow-up. Furthermore, abortions (1), perinatal (1) and infantile death (2) occurred only in children of WWE / Doutorado / Neurologia

In this 15 year follow up study in a Chinese population, we confirmed that maternal gestational diabetic status significantly increased women’s future cardiometabolic risk. Glycaemic levels below the current criteria for a positive screening test for gestational diabetes and for the diagnosis of gestational diabetes still significantly predict women’s future risk. In utero hyperinsulinaemia, which caused by an intrauterine hyperglycaemic environment, was found to predict children’s AGT and adolescents’ overweight and MetS. The results had important implication that the current diagnostic criteria for gestational diabetes may not be discriminative in predicting both the mothers and their children’s future cardiometabolic risk. Although recent research has re-visited and emphasised on the diagnostic criteria of gestational diabetes which best predicted adverse pregnancy outcome, future study should also scrutinise on the optimal glycaemic threshold, either in screening or diagnostic test, that relate to the mothers’ and children offspring’s long term cardiometabolic risk. / Tam, Wing Hung. / Thesis (M.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 119-146). / Abstract also in Chinese. / LIST OF TABLES --- p.xxii / LIST OF FIGURES --- p.xxv / LIST OF ABBREVIATIONS --- p.xxvi / Chapter Chapter 1 --- Gestational diabetes & future cardiometabolic risk - an overview / Chapter 1.1 --- Historical background --- p.2 / Chapter 1.2 --- Pregnancy physiology vs. gestational diabetes --- p.5 / Chapter 1.3 --- Diabetes mellitus - a global epidemic --- p.6 / Chapter 1.4 --- History of gestational diabetes & progression to Type 2 DM --- p.7 / Chapter 1.5 --- History of gestational diabetes & cardiometabolic risk --- p.8 / Chapter 1.6 --- Type 2 DM among children and adolescents --- p.9 / Chapter 1.7 --- Type 2 DM among offspring of mothers with gestational diabetes --- p.10 / Chapter 1.8 --- Cardiometabolic risk in children exposed to maternal gestational diabetes --- p.12 / Chapter 1.9 --- Long term follow up on mothers & children cohort --- p.12 / Chapter Chapter 2 --- Research methodology / Chapter 2.1 --- Subjects --- p.16 / Chapter 2.2 --- Obstetric and neonatal information --- p.18 / Chapter 2.2.1 --- Maternal glycaemic indices at pregnancy --- p.18 / Chapter 2.2.2 --- Umbilical cord blood C-peptide & insulin levels --- p.18 / Chapter 2.2.3 --- Definition of antenatal variables --- p.19 / Chapter 2.3 --- Follow up assessment of the mothers --- p.19 / Chapter 2.4 --- Follow up assessment of the children and adolescents --- p.22 / Chapter 2.5 --- Definition of abnormal glucose tolerance and metabolic syndrome --- p.24 / Chapter 2.5.1 --- Definition of abnormal glucose tolerance --- p.24 / Chapter 2.5.2 --- Definition of metabolic syndrome in adult --- p.24 / Chapter 2.5.3 --- Definition of metabolic syndrome in adolescent --- p.25 / Chapter 2.6 --- Determination of insulin resistance and pancreatic beta cell function --- p.26 / Chapter 2.6.1 --- Definition of insulin resistance --- p.26 / Chapter 2.6.2 --- Definition of pancreatic beta cell function --- p.26 / Chapter 2.6.3 --- Measurement of insulin resistance and pancreatic β-cell function --- p.27 / Chapter 2.7 --- Statistical analysis --- p.31 / Chapter 2.7.1 --- Statistical programme --- p.31 / Chapter 2.7.2 --- Comparison between group differences --- p.31 / Chapter 2.7.3 --- General Linear Model --- p.32 / Chapter 2.7.4 --- Multivariate logistic regression --- p.33 / Chapter 2.7.5 --- Receiver operating characteristic analysis --- p.37 / Chapter 2.8 --- Ethics approval --- p.41 / Chapter 2.9 --- Funding --- p.42 / Chapter Chapter 3 --- History of gestational diabetes and women’s future cardiometabolic risk / Chapter 3.1 --- Maternal clinical parameters at the index pregnancy --- p.44 / Chapter 3.2 --- Maternal cardiometabolic status at 8 years post-delivery --- p.45 / Chapter 3.3 --- Maternal cardiometabolic status at 15 years post-delivery --- p.49 / Chapter 3.4 --- Prediction of cardiometabolic risk by maternal gestational diabetic status --- p.50 / Chapter 3.4.1 --- Abnormal glucose tolerance and metabolic syndrome at 8 years by maternal gestational diabetic status --- p.52 / Chapter 3.4.2 --- Abnormal glucose tolerance, DM, hypertension and metabolic syndrome at 15 years by maternal gestational diabetic status --- p.52 / Chapter 3.5 --- The role of insulin resistance in predicting women’s DM and metabolic syndrome --- p.55 / Chapter 3.6 --- Discussion --- p.57 / Chapter 3.7 --- Conclusion --- p.62 / Chapter Chapter 4 --- Glycaemic variables measured at mid-gestation of the index pregnancy predict women’s future cardiometabolic risk / Chapter 4.1 --- Glycaemic levels in pregnancy and perinatal outcome --- p.64 / Chapter 4.2 --- Glycaemic levels in pregnancy and women’s future cardiometabolic risk --- p.65 / Chapter 4.2.1 --- Prediction of women’s cardiometabolic risk at 8 and 15-year --- p.66 / Chapter 4.2.2 --- Optimal cut-off levels in predicting women’s future cardio- metabolic risk --- p.69 / Chapter 4.3 --- Discussion --- p.75 / Chapter 4.4 --- Conclusion --- p.78 / Chapter Chapter 5 --- Maternal gestational diabetes and offspring’s cardiometabolic risk / Chapter 5.1 --- Offspring’s cardiometabolic risk at 8 years age --- p.80 / Chapter 5.1.1 --- Baseline characteristics at pregnancy and delivery --- p.80 / Chapter 5.1.2 --- Children’s clinical and biochemical parameters at 8 years age --- p.82 / Chapter 5.2 --- Offspring’s cardiometabolic risk at 15 years age --- p.84 / Chapter 5.2.1 --- Adolescents’ clinical and biochemical parameters at 15 years age --- p.84 / Chapter 5.2.2 --- Clinical parameters of adolescents with abnormal glucose tolerance --- p.84 / Chapter 5.3 --- Discussion --- p.88 / Chapter 5.4 --- Conclusion --- p.90 / Chapter Chapter 6 --- In utero hyperinsulinaemia and offspring’s cardiometabolic risk / Chapter 6.1 --- Umbilical cord blood insulin and C-peptide --- p.92 / Chapter 6.1.1 --- Umbilical cord insulin and C-peptide concentrations in the original cohort --- p.92 / Chapter 6.1.2 --- Determination of in utero hyperinsulinaemia by umbilical cord insulin and C-peptide levels --- p.95 / Chapter 6.2 --- The effect of in utero hyperinsulinaemia on children’s abnormal glucose tolerance at 8 years of age --- p.98 / Chapter 6.2.1 --- Receiver operating characteristic analysis --- p.98 / Chapter 6.2.2 --- Logistic regression analysis --- p.98 / Chapter 6.3 --- The effect of in utero hyperinsulinaemia on adolescents’ cardio- metabolic risk at 15years of age --- p.102 / Chapter 6.3.1 --- Logistic regression analysis --- p.102 / Chapter 6.4 --- Discussion --- p.105 / Chapter 6.5 --- Conclusion --- p.108 / Chapter Chapter 7 --- Summary and conclusion / Chapter 7.1 --- Summary of the thesis --- p.110 / Chapter 7.1.1 --- Women’s long term cardiometabolic risk after a pregnancy with gestational diabetes --- p.110 / Chapter 7.1.2 --- The long term cardiometabolic risk of children born to mothers who had gestational diabetes --- p.111 / Chapter 7.1.3 --- New findings from the studies and their implications --- p.111 / Chapter 7.2 --- Strength and weakness in the study --- p.113 / Chapter 7.2.1 --- Unique cohort from universal screening --- p.113 / Chapter 7.2.2 --- Study design --- p.113 / Chapter 7.2.3 --- Response rate and loss to follow up --- p.114 / Chapter 7.2.4 --- Treatment effect of gestational diabetes --- p.115 / Chapter 7.3 --- Issues of future research --- p.115 / Chapter 7.3.1 --- Follow up study on the HAPO cohort --- p.115 / Chapter 7.3.2 --- Opportunity for international collaboration --- p.117 / Chapter 7.4 --- Conclusion --- p.118 / REFERENCES --- p.119

Fetal growth restriction (FGR) is a common and potentially life-threatening complication that affects 5-10% of human pregnancies. Maternal genetic predisposition and fetal male sex are known risk factors, but the underlying mechanisms are unknown. To study a known maternal genetic risk factor and the impact of fetal sex, we employed a published transgenic (TG) mouse model, which was designed to mimic a common human angiotensinogen (AGT) promoter variant associated with a 20% increase in circulating AGT levels. We hypothesized that TG dams would deliver growth restricted pups and that the underlying mechanism would be related to differences in maternal uterine pregnancy-induced vascular remodeling, abnormal blood flow to the placenta, and placental damage. In addition, since growth restricted human males are at an increased risk of developing adult onset hypertension, which has been associated with reduced nephron development, we tested for developmental programming in our mouse model and the impact of fetal sex. Our results show that TG dams have reduced uterine and placental angiogenesis when their pups were males, but relatively normal angiogenesis in the female siblings compared with wild-type controls. The uterine placental bed in TG dams had abnormal pro-angiogenic/anti-angiogenic expression ratios that were related to differences in uterine natural killer cell activation and fetal sex. The abnormal phenotype could be rescued by delivering vascular endothelial growth factor (VEGF) to uterine endothelial cells. Male progeny from TG dams had abnormal kidney epigenetic changes, fewer nephrons as adults, and they developed stress-induced hypertension. We conclude that the combination of maternal genetic risk and fetal male sex affect uteroplacental angiogenesis leading to FGR and the programming of stress-induced hypertension.

[Truncated abstract] Increased incidence of hypertension, insulin resistance, obesity and dyslipidemia, collectively referred to as the metabolic syndrome, has been linked to low birth weight, an indicator of a poor fetal environment. This association reflects developmental programming, a process by which organ systems are affected during early development such that disease states are more likely to emerge in adult life. Fetal glucocorticoid overexposure is thought to be a key factor that mediates developmental programming. Accordingly, maternal treatment with the synthetic glucocorticoid dexamethasone retards fetal growth and leads to delayed puberty, hypertension, hyperinsulinemia, and hyperleptinemia, either with or without increased adiposity, in adult offspring. Importantly, the postnatal environment can either amplify or attenuate the long-term outcome of developmental programming. The focus of this thesis was whether adverse developmental programming outcomes can be attenuated by the postnatal environment and thus provide therapeutic potential. Specifically, the effects of a postnatal diet rich in omega-3 fatty acids on glucocorticoid-induced developmental programming outcomes was investigated. ... The adipocyte phenotype was examined in Study 6, with hyperleptinaemia evident in offspring at 6 and 12 months of age in dexamethasone-exposed animals on a standard omega-3 diet, but this effect was prevented by a high omega-3 diet. The pattern of plasma leptin was paralleled by changes in leptin mRNA in retroperitoneal fat. Similarly, plasma levels of the inflammatory markers IL-6 and IL-1β were upregulated by prenatal glucocorticoid exposure and these were attenuated by postnatal dietary omega-3 fatty acids. Overall, omega-3 ingestion reduced adiposity, as indicated by measures of body composition. In conclusion, the studies presented in this thesis demonstrate for the first time that many of the detrimental effects of excess glucocorticoid exposure in utero on the adult phenotype can be attenuated by a postnatal diet rich in omega-3 fatty acids. This beneficial effect of omega-3 fatty acids was associated with a reversal of some (e.g. adiposal leptin) but not all (e.g. renal GR) 'programmed' changes in gene expression. These findings raise the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans.

The placenta plays a vital role in a healthy pregnancy by supporting the intricacies of fetal development. Over 10% of pregnancies experience impaired placental function, resulting in the loss of critical neuroactive steroids the fetal brain cannot yet make, thus leaving them vulnerable to perinatal brain injury and abnormal neurodevelopment. However, this vulnerability is not always equal. Many neurodevelopmental disorders exhibit a sex bias in incidence and severity. I hypothesize that loss of placental support during pregnancy results in sex differences in both behavioral presentation as well as on the cellular and transcriptomic levels. Utilizing the akr1c14cyp19aKO (plKO) mouse model, which features placenta-specific allopregnanolone (ALLO) knockdown, I investigated the sex specific impact of placental hormones on cerebellar development. Here I show that placental ALLO is essential for cerebellar white matter development and inflammatory regulation via microglial function. Male mice without placental ALLO exhibit signs of placental inflammation, accelerated postnatal myelination, and defects in microglial phagocytosis of excess myelin. Alternatively, females seem to be more resilient with a progressive anti-inflammatory profile across development and reduced myelination. Additionally male plKO show autism-like behaviors such as deficits in social behavior and increased stereotyped behavior. The females do not exhibit this phenotype. My main goals were threefold; to investigate how male and female inflammatory profiles differ and where this difference originates, to investigate how this inflammation impacts microglia and thereby oligodendrocytes, and how I can alter microglial function in a way to improve plKO outcomes. Mechanistically, these changes appear to be in part due to baseline sex differences in response to inflammatory stimuli which prime microglia to differentially support the surrounding white matter. Together, this work supports a novel link between placental ALLO loss, microglial function, and sex specific presentation of neurodevelopmental disorders.

Studies of humans and domestic animals have shown that there is a linkage between the neonatal and post-natal health of an individual and its uterine environment during gestation. However, very little information exists for sheep and there have been no studies that have directly examined the stage of gestation at which such effects could be introduced to the conceptus. In the present study, pure-breed embryos were transferred within and reciprocally between large (Suffolk: S) and small (Cheviot: C) breeds of sheep to establish different uterine environments; SinS (large control), SinC (restricted environment), CinS (luxurious environment) and CinC (small control) and their effects upon embryonic, fetal, neonatal and post-natal development and glucose metabolism of lambs were examined. By Day 19 of gestation, conceptuses (embryo and trophoblast) developing in a restricted uterine environment (SinC) were smaller (P<0.05) than in control (SinS). The head length of SinC fetuses was smaller (P<0.05) than in SinS fetuses on Day 55 of gestation and SinC lambs were lighter and smaller (P<0.05) than SinS lambs at birth. During subsequent post-natal life, there was no difference (P>0.05) in the growth rate of SinC and SinS lambs. The liveweight and body dimensions of SinC lambs were lower (P<0.05) than SinS lambs until 9 weeks and 12 weeks of age, respectively. Day 19 peri-implantation embryos and trophoblasts that developed in a luxurious environment were bigger than in control (CinC). However, CinS fetal size did not differ (P>0.05) from CinC fetuses by Day 55 of gestation. There was no difference (P>0.05) in the birthweight and body dimensions of lambs born from these two groups. Dimension of the placentas of SinC and SinS or CinS and CinC did not differ (P<0.05) during gestation or at lambing. Concentrations of ovine placental lactogen (oPL), progesterone, insulin-like growth factor-1 (IGF-1), glucose and free fatty acid (FFA) differed between uterine environments. During glucose challenge tests, there were no differences in the concentrations of glucose and insulin, between SinC and SinS female lambs, however, glucose concentrations declined more rapidly (P<0.05) in CinS than CinC female lambs at one year of age. It was concluded that restricted uterine environment affects embryonic, fetal and neonatal development of lambs, and that these effects perpetuates until at least one year of age; but there was no effect upon glucose metabolism. Conversely, a luxurious uterine environment enhances the early development of embryos but had no effects upon subsequent fetal, neonatal and post-natal development; however glucose metabolism of post-natal female lambs was improved. It appears that these effects of uterine environment were mediated through the trophoblast during the early embryonic period and via the placenta during subsequent gestation. oPL, progesterone, IGF-1, glucose and FFA were implicated in feto-maternal dialogue. These results suggest that uterine environment significantly influences the biology of young sheep with possible economic consequences.

The consequences of early embryonic insults and how they affect subsequent life reflects the emerging concept of "fetal programming". The aim of this project is to study the effects of embryonic insults as they subsequently manifest themselves in adults, with emphasis on the heart and vasculature. My experiments establish that fetal programming operates on the bobwhite quail inducing similar changes as those observed in mammalians and other birds. The quail's fast development provides reliable data in a short period of time than other avian models (e.g. domestic chicken). Data on quail showed a correlation between egg mass and hatchling mass; where small eggs produce small hatchlings but a high mortality made it impractical as a stressor for this study. Hypoxia was used as a stressor during embryonic incubation, where it induced a low hatching weight in quail that was not observable in adult birds. Morphological measurements demonstrated an increased ventricular collagen content and reduced ventricular lumen in birds in adults incubated in hypoxia consistent with hypertension. The hematological analyzes showed few differences indicating organ remodeling instead of hematopoietic compensation. The assessment of vascular reactivity pointed out an impaired endothelium dependent relaxation commonly associated to hypertension in birds and mammals. Fetal programming could be a widespread response to an adverse prenatal environment in endotherms and the resulting data from this work contributes to our understanding of fetal programming in vertebrates and its long term consequences.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / O desenvolvimento da programação fetal é considerado um importante fator de risco para doenças não-transmissíveis da vida adulta, incluindo doença cardíaca coronariana. Com o objetivo de investigar a associação entre nutrição materna e o desenvolvimento das artérias coronárias (AC) em embriões de camundongos estadiados; embriões de camundongos C57BL/6 nos estádios de 16-23 foram retirados de mães alimentadas com dietas de proteína normal (NP) ou de baixa proteína (LP), e as AC foram estudadas. Embora os embriões LP possuam massa corporal menor, entretanto tinham taxas de crescimento cardíaco maior, quando comparados com os embriões NP. O Plexo subepicárdico foi observado no início do período pós-somítico (estádio 16) de embriões NP, enquanto que nos embriões LP apenas no estádio 17 (P <0,01), persistindo até o estádio 18 (P <0,01). As artérias coronárias foram detectadas inicialmente no estádio18 dos embriões NP, já nos embriões LP foram encontradas a partir do estádio 19 (P <0,01). Núcleos apoptóticos foram observados em torno do anel aórtico peritruncal no estádio 18 em embriões NP e LP. Células FLK1+ (Fetal Liver Kinase 1 = VEGFr2 = Vascular Endothelial Growth Factor Receptor 2) apresentaram uma distribuição homogênea nos embriões NP já no estádio 18, enquanto uma distribuição semelhante nos embriões LP foi visto apenas nos estádios 22 e 23. A restrição proteica materna em camundongos leva a um atraso no crescimento do coração no período embrionário modificando o desenvolvimento do plexo peritruncal subepicárdica e diminuindo a taxa de apoptose na região do futuro orifício coronariano. / Programming of fetal development is considered to be an important risk factor for non-communicable diseases of adulthood, including coronary heart disease (CHD). Aiming to investigate the association between maternal nutrition and the development of the coronary arteries (CA) in staged mice embryos, C57BL/6 mice embryos from stages 16 to 23 were taken from mothers fed a normal protein (NP) or low protein (LP) diet, and the CA were studied. Although the LP embryos had lower masses, they had faster heart growth rates when compared to the NP embryos. The subepicardial plexuses were observed earlier in the NP embryos (stage 20) than in the LP ones (stage 22) (P<0.01). Apoptotic nuclei were seen around the aortic peritruncal ring beginning at stage 18 in the NP and LP embryos. FLK1+ (fetal liver kinase 1 = VEGFr2 or vascular endothelial growth factor receptor 2) cells had a homogeneous distribution in the NP embryos as early as stage 18, whereas a similar distribution in the LP embryos was only seen at stages 22 and 23. Maternal protein restriction in mice leads to a delay in the growth of the heart in the embryonic period modifying the development of the subepicardial peritruncal plexus and the apoptosis in the future coronary orifice region.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / O desenvolvimento da programação fetal é considerado um importante fator de risco para doenças não-transmissíveis da vida adulta, incluindo doença cardíaca coronariana. Com o objetivo de investigar a associação entre nutrição materna e o desenvolvimento das artérias coronárias (AC) em embriões de camundongos estadiados; embriões de camundongos C57BL/6 nos estádios de 16-23 foram retirados de mães alimentadas com dietas de proteína normal (NP) ou de baixa proteína (LP), e as AC foram estudadas. Embora os embriões LP possuam massa corporal menor, entretanto tinham taxas de crescimento cardíaco maior, quando comparados com os embriões NP. O Plexo subepicárdico foi observado no início do período pós-somítico (estádio 16) de embriões NP, enquanto que nos embriões LP apenas no estádio 17 (P <0,01), persistindo até o estádio 18 (P <0,01). As artérias coronárias foram detectadas inicialmente no estádio18 dos embriões NP, já nos embriões LP foram encontradas a partir do estádio 19 (P <0,01). Núcleos apoptóticos foram observados em torno do anel aórtico peritruncal no estádio 18 em embriões NP e LP. Células FLK1+ (Fetal Liver Kinase 1 = VEGFr2 = Vascular Endothelial Growth Factor Receptor 2) apresentaram uma distribuição homogênea nos embriões NP já no estádio 18, enquanto uma distribuição semelhante nos embriões LP foi visto apenas nos estádios 22 e 23. A restrição proteica materna em camundongos leva a um atraso no crescimento do coração no período embrionário modificando o desenvolvimento do plexo peritruncal subepicárdica e diminuindo a taxa de apoptose na região do futuro orifício coronariano. / Programming of fetal development is considered to be an important risk factor for non-communicable diseases of adulthood, including coronary heart disease (CHD). Aiming to investigate the association between maternal nutrition and the development of the coronary arteries (CA) in staged mice embryos, C57BL/6 mice embryos from stages 16 to 23 were taken from mothers fed a normal protein (NP) or low protein (LP) diet, and the CA were studied. Although the LP embryos had lower masses, they had faster heart growth rates when compared to the NP embryos. The subepicardial plexuses were observed earlier in the NP embryos (stage 20) than in the LP ones (stage 22) (P<0.01). Apoptotic nuclei were seen around the aortic peritruncal ring beginning at stage 18 in the NP and LP embryos. FLK1+ (fetal liver kinase 1 = VEGFr2 or vascular endothelial growth factor receptor 2) cells had a homogeneous distribution in the NP embryos as early as stage 18, whereas a similar distribution in the LP embryos was only seen at stages 22 and 23. Maternal protein restriction in mice leads to a delay in the growth of the heart in the embryonic period modifying the development of the subepicardial peritruncal plexus and the apoptosis in the future coronary orifice region.