Advantageous early-life environments cushion the genetic risk for ischemic heart disease.

In one of the first papers on the impact of early-life conditions on individuals' health in older age, Barker and Osmond [Lancet, 327, 1077-1081 (1986)] show a strong positive relationship between infant mortality rates in the 1920s and ischemic heart disease in the 1970s. We merge historical data on infant mortality rates to 370,000 individual records in the UK Biobank using information on local area and year of birth. We replicate the association between the early-life infant mortality rate and later-life ischemic heart disease in our sample. We then go "beyond Barker," by showing considerable genetic heterogeneity in this association that is robust to within-area as well as within-family analyses. We find no association between the polygenic index and heart disease in areas with the lowest infant mortality rates, but a strong positive relationship in areas characterized by high infant mortality. These findings suggest that advantageous environments can cushion one's genetic disease risk.

Preeclampsia: Short- and Long-Term Effects.

Does our time inside the womb predict our future? Evidence suggests that the environment in the womb plays a powerful role in predicting specific adult diseases. The fetus is constantly responding and adapting to the intrauterine environment by a process called programming. Toxic exposures, such as nutritional deficits and hypoxia, can affect fetal development and increase the risk for specific diseases that manifest later in our adult life. Preeclampsia (PE) is one disorder that results in a less-than-optimal environment for the growing fetus. It is pregnancy-specific and defined as new-onset hypertension after 20 weeks' gestation in the presence of maternal multiorgan dysfunction. To the best of our understanding, the pathogenesis is multifactorial and involves dysfunction of the placenta and the vascular, renal, and immunological systems. Treatment options are limited and may result in adverse outcomes for the fetus and newborn. Preeclampsia is a major contributor to perinatal and maternal morbidity and mortality worldwide, thus generating a significant healthcare burden. Research continues to demonstrate that mothers and infants affected by PE are at increased susceptibility to chronic conditions such as cardiovascular, renal, metabolic, and neurological diseases. More efforts are needed to further understand this disease. Efforts to increase awareness will help improve clinical outcomes for both mothers and infants.

Invited Commentary: Beyond Barker-Mothers Are the Ones at Risk.

Dr. David Barker hypothesized that low birth weight (LBW) is the result of inadequate fetal nutrition, leading to increased risk of cardiovascular disease (CVD) in the offspring. This hypothesis has stimulated thousands of reports on low birth weight (LBW) and CVD risk. One problem with this association is that many LBW infants are small because they are preterm, not growth-restricted. A second problem is that maternal CVD risk factors confound the association. In an accompanying article, Lu et al. (Am J Epidemiol. 2023;192(6):866-877) address both concerns. Using population data from Sweden and Denmark, the authors estimated CVD incidence among offspring born small for gestational age (SGA). The smallest 3% had a CVD hazard ratio of 1.44 (95% confidence interval: 1.38, 1.51). Even this moderate risk mostly evaporated in sibship analysis, which controlled for unmeasured maternal CVD risk factors (hazard ratio = 1.11, 95% confidence interval: 0.99, 1.25). The risk highlighted by Barker is negligible, especially when compared with a more urgent health issue-cardiovascular risk in women with pregnancy complications. Mothers of SGA infants have up to a 3-fold CVD risk, and mothers with preeclampsia and preterm delivery have up to a 9-fold risk. Pregnancy complications thus provide an early marker of a woman's propensity to develop CVD, and perhaps an opportunity for early intervention. From a public health perspective, Barker's hypothesis about CVD risk in LBW offspring is less compelling than the question of CVD risk among mothers with pregnancy complications. This article is part of a Special Collection on ABC.

Maternal smoking during pregnancy, offspring smoking, adverse childhood events, and risk of major depression: a sibling design study.

BACKGROUND: Evidence of a biologically plausible association between maternal smoking during pregnancy (MSP) and the risk of depression is discounted by null findings from two sibling studies. However, valid causal inference from sibling studies is subject to challenges inherent to human studies of MSP and biases particular to this design. We addressed these challenges in the first sibling study of MSP and depression conducted among adults past the peak age for the onset of depression, utilizing a prospectively collected and biologically validated measure of MSP and accounting for non-shared as well as mediating factors. METHODS: We fit GEE binomial regression models to correct for dependence in the risk of depression across pregnancies of the same mother. We also fit marginal structural models (MSM) to estimate the controlled direct effect of MSP on depression that is not mediated by the offspring's smoking status. Both models allow the estimation of within- and between-sibling risk ratios. RESULTS: The adjusted within-sibling risk ratios (RRW) from both models (GEE: RRW = 1.97, CI 1.16-3.32; MSM: RRW = 2.08, CI 1.04-4.17) evinced an independent association between MSP and risk of depression. The overall effects from a standard model evinced lower associations (GEE: RRT = 1.12, CI 0.98-1.28; MSM: RRT = 1.18, CI 1.01-1.37). CONCLUSIONS: Based on within-sibling information free of unmeasured shared confounders and accounting for a range of unshared factors, we found an effect of MSP on the offspring's risk of depression. Our findings, should they be replicated in future studies, highlight the importance of considering challenges inherent to human studies of MSP and affective disorders.

Barker's Hypothesis Among the Global Poor: Positive Long-Term Cardiovascular Effects of in Utero Famine Exposure.

An influential literature on the Developmental Origins of Health and Disease (DOHaD) has documented that poor conditions in utero lead to higher risk of cardiovascular disease at older ages. Evidence from low-income countries (LICs) has hitherto been missing, despite the fact that adverse in utero conditions are far more common in LICs. We find that Malawians exposed in utero to the 1949 Nyasaland famine have better cardiovascular health 70 years later. These findings highlight the potential context specificity of the DOHaD hypothesis, with in utero adversity having different health implications among aging LIC individuals who were exposed to persistent poverty.

Childhood adherence to a potentially healthy and sustainable Nordic diet and later overweight: The Norwegian Mother, Father and Child Cohort Study (MoBa).

The New Nordic Diet (NND) is a potentially healthy and sustainable dietary pattern represented by locally available and traditionally consumed foods in the Northern countries. The diet has been commonly examined in adult populations, but less is known regarding its potential associations with overweight/obesity in children. We have previously developed child diet scores measuring compliance to the NND at child age 6 and 18 months and 3 and 7 years. In this study, we aimed to describe child and maternal characteristics and assess potential associations between the age-specific diet scores and child overweight at 8 years. This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa), including 14,989 mother-child pairs and uses data from the Medical Birth Registry of Norway (MBRN). The scores measured NND compliance as a total score and categorized into low, medium and high NND compliance at each age point. Using logistic regression models, we investigated the association between each age-specific score and the odds of overweight at 8 years. In crude analyses, adherence to the NND at 6 months was inversely associated with odds of overweight at 8 years in the continuous score (odds ratio = 0.95, 95% CI [0.91, 0.98]) and when comparing high versus low NND adherence (odds ratio = 0.81, 95% CI [0.70, 0.94]). The association was almost entirely attenuated in the adjusted models. In conclusion, child NND adherence up to 7 years of age was not associated with odds of overweight at 8 years in adjusted analyses.

Risks of cause-specific mortality in offspring of pregnancies complicated by hypertensive disease of pregnancy.

BACKGROUND: Fetal environment has a substantial influence on an individual's health throughout their life course. Animal models of hypertensive disease of pregnancy have demonstrated adverse health outcomes among offspring exposed to hypertensive disease of pregnancy in utero. Although there are numerous descriptions of the neonatal, infant, and pediatric outcomes of human offspring affected by hypertensive disease of pregnancy, there are few data in US populations on later life outcomes, including mortality. OBJECTIVE: To assess risk for early mortality among offspring of pregnancies complicated by hypertensive disease of pregnancy. STUDY DESIGN: This is a retrospective cohort study of offspring born to women with singleton or twin pregnancies between 1947 and 1967 with birth certificate information in the Utah Population Database. We identified offspring from delivery diagnoses of gestational hypertension, preeclampsia, or eclampsia. Offspring from these pregnancies (exposed) were matched to offspring of pregnancies without hypertensive disease of pregnancy (unexposed) by maternal age at delivery, birth year, sex, and multiple gestation. We also identified unexposed siblings of exposed offspring for a separate sibling analysis. Mortality follow-up of all offspring continued through 2016, at which time they would have been 49-69 years old. Adjusted hazard ratios for cause-specific mortality comparing exposed with unexposed offspring were estimated using Cox proportional hazard models. RESULTS: We compared mortality risks for 4050 exposed offspring and 6989 matched unexposed offspring from the general population and 7496 unexposed siblings. Mortality risks due to metabolic, respiratory, digestive, nervous, and external causes of death did not differ between exposed and unexposed groups. Mortality risks from cardiovascular disease were greater in exposed offspring compared with unexposed offspring (adjusted hazard ratio, 1.57; 95% confidence interval, 1.16-2.12). In sex-specific models among the general population, cardiovascular disease mortality was significantly associated with exposure among male patients (adjusted hazard ratio, 1.92; 95% confidence interval, 1.27-2.88) but not among female patients (adjusted hazard ratio, 0.97; 95% confidence interval, 0.81-1.94). An interaction between hypertensive disease of pregnancy exposure and birth order on cardiovascular disease mortality was significant (P=.047), suggesting that the effect of hypertensive disease of pregnancy on cardiovascular disease mortality increased with higher birth order. Among siblings, the association between hypertensive disease of pregnancy exposure and cardiovascular disease mortality was not significant (adjusted hazard ratio, 1.39; 95% confidence interval, 0.99-1.95), and this was also true for sex-specific analyses of males (adjusted hazard ratio, 1.26; 95% confidence interval, 0.81-1.94) and females (adjusted hazard ratio, 1.71; 95% confidence interval, 0.96-3.04). As in the general population, there was a significant interaction between hypertensive disease of pregnancy exposure and birth order on cardiovascular disease mortality (P=.011). CONCLUSION: In a US population, overall mortality risks are greater for offspring of pregnancies complicated by hypertensive disease of pregnancy compared with unexposed offspring. Among siblings, there was not a significant association between hypertensive disease of pregnancy exposure and cardiovascular disease mortality.

Synergies between the Developmental Origins of Health and Disease framework and multiple branches of evolutionary anthropology.

The Developmental Origins of Health and Disease (DOHaD) hypothesis derives from the epidemiological and basic/mechanistic health sciences. This well-supported hypothesis holds that environment during the earliest stages of life-pre-conception, pregnancy, infancy-shapes developmental trajectories and ultimately health outcomes across the lifespan. Evolutionary anthropologists from multiple subdisciplines are embracing synergies between the DOHaD framework and developmentalist approaches from evolutionary biology. Even wider dissemination and employment of DOHaD concepts will benefit evolutionary anthropological research. Insights from experimental DOHaD work will focus anthropologists' attention on biochemical/physiological mechanisms underpinning observed links between growth/health/behavioral outcomes and environmental contexts. Furthermore, the communication tools and wide public appeal of developmentalist health scientific research may facilitate the translation/application of evolutionary anthropological findings. Evolutionary Anthropology, in turn, can increase mainstream DOHaD research's use of evolutionary theory; holistic, longitudinal, and community-based perspectives; and engagement with populations whose environmental exposures differ from those most commonly studied in the health sciences.

Association of birth outcomes and postnatal growth with adult leukocyte telomere length: Data from New Delhi Birth Cohort.

Born small for gestational age due to undernutrition in utero and subsequent catch-up growth is associated with risk of developing chronic diseases in adulthood. Telomere length has been shown to be a predictor of these age-related diseases and may be a link between birth size, a surrogate for foetal undernutrition, and adult chronic diseases. We assessed the relationship of leukocyte telomere length in adult life with birth outcomes and serial change in body mass index (BMI) from birth to adulthood. Leukocyte relative telomere length (RTL) was measured by MMqPCR in 1,309 subjects from New Delhi Birth Cohort who participated in two phases of the study between 2006-2009 (Phase 6) and 2012-2015 (Phase 7) at a mean age of 39.08 (±3.29), and its association with birth outcomes and conditional BMI gain at 2, 11, and 29 years was assessed in a mixed regression model. We did not find any significant association of RTL with body size at birth including birthweight, birth length, and birth BMI. Gestational age was positively associated with RTL (P = .017, multivariate model: P = .039). Conditional BMI gain at 2 and 11 years was not associated with RTL. BMI gain at 29 year was negatively associated with RTL in multivariate model (P = .015). Born small for gestational age was not associated with RTL in adulthood. Leukocyte telomere attrition was observed in those born before 37 weeks of gestational age as well as in those who gained weight as adults, which may predispose to chronic diseases.

Air pollution and the fetal origin of disease: A systematic review of the molecular signatures of air pollution exposure in human placenta.

BACKGROUND: Fetal development is a crucial window of susceptibility in which exposure-related alterations can be induced on the molecular level, leading to potential changes in metabolism and development. The placenta serves as a gatekeeper between mother and fetus, and is in contact with environmental stressors throughout pregnancy. This makes the placenta as a temporary organ an informative non-invasive matrix suitable to investigate omics-related aberrations in association with in utero exposures such as ambient air pollution. OBJECTIVES: To summarize and discuss the current evidence and define the gaps of knowledge concerning human placental -omics markers in association with prenatal exposure to ambient air pollution. METHODS: Two investigators independently searched the PubMed, ScienceDirect, and Scopus databases to identify all studies published until January 2017 with an emphasis on epidemiological research on prenatal exposure to ambient air pollution and the effect on placental -omics signatures. RESULTS: From the initial 386 articles, 25 were retained following an a priori set inclusion and exclusion criteria. We identified eleven studies on the genome, two on the transcriptome, five on the epigenome, five on the proteome category, one study with both genomic and proteomic topics, and one study with both genomic and transcriptomic topics. Six studies discussed the triple relationship between exposure to air pollution during pregnancy, the associated placental -omics marker(s), and the potential effect on disease development later in life. So far, no metabolomic or exposomic data discussing associations between the placenta and prenatal exposure to air pollution have been published. CONCLUSIONS: Integration of placental biomarkers in an environmental epidemiological context enables researchers to address fundamental questions essential in unraveling the fetal origin of disease and helps to better define the pregnancy exposome of air pollution.

Discrete Barker Frailty and Warped Mortality Dynamics at Older Ages.

We develop a discrete variant of a general model for adult mortality influenced by the delayed impact of early conditions on adult health and mortality. The discrete variant of the model builds on an intuitively appealing interpretation of conditions that induce delayed effects and is an extension of the discrete form of the standard frailty model with distinct implications. We show that introducing delayed effects is equivalent to perturbing adult mortality patterns with a particular class of time-/age-varying frailty. We emphasize two main results. First, populations with delayed effects could experience unchanging or increasing adult mortality even when background mortality has been declining for long periods of time. Although this phenomenon also occurs in a regime with standard frailty, the distortions can be more severe under a regime with Barker frailty. As a consequence, conventional interpretations of the observed rates of adult mortality decline in societies that experience Barker frailty may be inappropriate. Second, the observed rate of senescence (slope of adult mortality rates) in populations with delayed effects could increase, decrease, or remain steady over time and across adult ages even though the rate of senescence of the background age pattern of mortality is time- and age-invariant. This second result implies that standard interpretations of empirical estimates of the slope of adult mortality rates in populations with delayed effects may be misleading because they can reflect mechanisms other than those inducing senescence as conventionally understood in the literature.

Dietary change mediates relationships between stress during pregnancy and infant head circumference measures: the QF2011 study.

Prenatal maternal stress can adversely affect birth outcomes, likely reflecting effects of maternal stress hormones on fetal development. Maternal stress might also induce behavioural changes, such as dietary change, that might influence fetal development. Few studies have documented relationships between stress and dietary change in pregnancy. We analysed stress and dietary change among 222 pregnant women exposed to the 2011 Queensland Floods. We assessed women's objective hardship, subjective distress and cognitive appraisal of the disaster; changes in their diets and their associations with infants' gestational age, weight, length and head circumference at birth, head circumference to birth length ratio (HC/BL) and ponderal index. Greater objective hardship was correlated with more negative dietary change, skipped meals and skipped multivitamins. There were no direct effects of stress or dietary change on birth outcomes. However, we observed an interactive effect of dietary change and exposure timing on head circumference for gestational age (HC for GA) (p = 0.010) and a similar trend for HC/BL (p = 0.064). HC for GA and HC/BL were larger among children whose mothers experienced negative changes to their diet in early pregnancy compared with later pregnancy, consistent with a 'head-sparing' response with early gestation exposure. Further analyses indicated that dietary change mediates the relationship between objective hardship because of the floods and these outcomes. This is the first report of relationships among an independent stressor, dietary change and birth outcomes. It highlights another possible mechanism in the relationship between prenatal maternal stress and child development that could guide future research and interventions.

Alcohol-Induced Developmental Origins of Adult-Onset Diseases.

Fetal alcohol exposure may impair growth, development, and function of multiple organ systems and is encompassed by the term fetal alcohol spectrum disorders (FASD). Research has so far focused on the mechanisms, prevention, and diagnosis of FASD, while the risk for adult-onset chronic diseases in individuals exposed to alcohol in utero is not well explored. David Barker's hypothesis on Developmental Origins of Health and Disease (DOHaD) suggests that insults to the milieu of the developing fetus program it for adult development of chronic diseases. In the 25 years since the introduction of this hypothesis, epidemiological and animal model studies have made significant advancements in identifying in utero developmental origins of chronic adult-onset diseases affecting cardiovascular, endocrine, musculoskeletal, and psychobehavioral systems. Teratogen exposure is an established programming agent for adult diseases, and recent studies suggest that prenatal alcohol exposure correlates with adult onset of neurobehavioral deficits, cardiovascular disease, endocrine dysfunction, and nutrient homeostasis instability, warranting additional investigation of alcohol-induced DOHaD, as well as patient follow-up well into adulthood for affected individuals. In utero epigenetic alterations during critical periods of methylation are a key potential mechanism for programming and susceptibility of adult-onset chronic diseases, with imprinted genes affecting metabolism being critical targets. Additional studies in epidemiology, phenotypic characterization in response to timing, dose, and duration of exposure, as well as elucidation of mechanisms underlying FASD-DOHaD inter relation, are thus needed to clinically define chronic disease associated with prenatal alcohol exposure. These studies are critical to establish interventional strategies that decrease incidence of these adult-onset diseases and promote healthier aging among individuals affected with FASD.

The impact of birth weight on cardiovascular disease risk in the Women's Health Initiative.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is among the leading causes of morbidity and mortality worldwide. Traditional risk factors predict 75-80% of an individual's risk of incident CVD. However, the role of early life experiences in future disease risk is gaining attention. The Barker hypothesis proposes fetal origins of adult disease, with consistent evidence demonstrating the deleterious consequences of birth weight outside the normal range. In this study, we investigate the role of birth weight in CVD risk prediction. METHODS AND RESULTS: The Women's Health Initiative (WHI) represents a large national cohort of post-menopausal women with 63,815 participants included in this analysis. Univariable proportional hazards regression analyses evaluated the association of 4 self-reported birth weight categories against 3 CVD outcome definitions, which included indicators of coronary heart disease, ischemic stroke, coronary revascularization, carotid artery disease and peripheral arterial disease. The role of birth weight was also evaluated for prediction of CVD events in the presence of traditional risk factors using 3 existing CVD risk prediction equations: one body mass index (BMI)-based and two laboratory-based models. Low birth weight (LBW) (<6 lbs.) was significantly associated with all CVD outcome definitions in univariable analyses (HR = 1.086, p = 0.009). LBW was a significant covariate in the BMI-based model (HR = 1.128, p < 0.0001) but not in the lipid-based models. CONCLUSION: LBW (<6 lbs.) is independently associated with CVD outcomes in the WHI cohort. This finding supports the role of the prenatal and postnatal environment in contributing to the development of adult chronic disease.

Developmental Origins of Hypoxic Pulmonary Hypertension and Systemic Vascular Dysfunction: Evidence from Humans.

Epidemiological studies have shown an association between pathologic events occurring during fetal/perinatal life and the development of cardiovascular and metabolic disease in adulthood. These observations have led to the so-called developmental origin of adult disease hypothesis. More recently, evidence has been provided that the pulmonary circulation is also an important target for the developmental programming of adult disease in both experimental animal models and in humans. Here we will review this evidence and provide insight into mechanisms that may play a pathogenic role.

Developmental Origins, Epigenetics, and Equity: Moving Upstream.

The Developmental Origins of Health and Disease and the related science of epigenetics redefines the meaning of what constitutes upstream approaches to significant social and public health problems. An increasingly frequent concept being expressed is "When it comes to your health, your zip code may be more important than your genetic code". Epigenetics explains how the environment-our zip code-literally gets under our skin, creates biological changes that increase our vulnerability for disease, and even children's prospects for social success, over their life course and into future generations. This science requires us to rethink where disease comes from and the best way to promote health. It identifies the most fundamental social equity issue in our society: that initial social and biological disadvantage, established even prior to birth, and linked to the social experience of prior generations, is made worse by adverse environments throughout the life course. But at the same time, it provides hope because it tells us that a concerted focus on using public policy to improve our social, physical, and economic environments can ultimately change our biology and the trajectory of health and social success into future generations.

Entangled lives: Implications of the developmental origins of health and disease hypothesis for bioarchaeology and the life course.

Epidemiological research since the 1980s has highlighted the consequences of early life adversity, particularly during gestation and early infancy, for adult health (the "Barker hypothesis"). The fast-evolving field of molecular epigenetics is providing explanatory mechanisms concerning phenotypic plasticity in response to developmental stressors and the accumulation of disease risk throughout life. In addition, there is now evidence for the heritability of poor health across generations via epigenetic modifications. This research has the potential to invoke a paradigmatic shift in how we interpret factors such as growth insults and immune response in past skeletal remains. It demonstrates that health cannot be understood in terms of immediate environmental circumstances alone. Furthermore, it requires both a theoretical and practical re-evaluation of disease biographies and the life course more generally. Individual life courses can no longer be regarded as discrete, bounded, life histories, with clearly defined beginning and end points. If socioeconomic circumstances can have intergenerational effects, including disease susceptibility and growth stunting, then individual biographies should be viewed as nested or "embedded" within the lives of others. This commingling of life courses may prove problematic to unravel; nevertheless, this review aims to consider the potential consequences for bioarchaeological interpretations. These include a greater consideration of: the temporal power of human skeletons and a life course approach to past health; infant health and the implications for maternal well-being; and the impact of non-proximate stressors (e.g., early life and ancestral environments) on the presence of health indicators.

The fascinating theory of fetal programming of adult diseases: A review of the fundamentals of the Barker hypothesis.

The theory of fetal programming of adult diseases was first proposed by David J.P. Barker in the eighties of the previous century, to explain the higher susceptibility of some people toward the development of ischemic heart disease. According to his hypothesis, poor maternal living conditions during gestation represent an important risk factor for the onset of atherosclerotic heart disease later in life. The analysis of the early phases of fetal development is a fundamental tool for the risk stratification of children and adults, allowing the identification of susceptible or resistant subjects to multiple diseases later in life. Here, we provide a narrative summary of the most relevant evidence supporting the Barker hypothesis in multiple fields of medicine, including neuropsychiatric disorders, such as Parkinson disease and Alzheimer disease, kidney failure, atherosclerosis, coronary heart disease, stroke, diabetes, cancer onset and progression, metabolic syndrome, and infectious diseases including COVID-19. Given the consensus on the role of body weight at birth as a practical indicator of the fetal nutritional status during gestation, every subject with a low birth weight should be considered an "at risk" subject for the development of multiple diseases later in life. The hypothesis of the "physiological regenerative medicine," able to improve fetal organs' development in the perinatal period is discussed, in the light of recent experimental data indicating Thymosin Beta-4 as a powerful growth promoter when administered to pregnant mothers before birth.

Maternal engineered nanomaterial exposure and fetal microvascular function: does the Barker hypothesis apply?

OBJECTIVE: The continued development and use of engineered nanomaterials (ENM) has given rise to concerns over the potential for human health effects. Although the understanding of cardiovascular ENM toxicity is improving, one of the most complex and acutely demanding "special" circulations is the enhanced maternal system to support fetal development. The Barker hypothesis proposes that fetal development within a hostile gestational environment may predispose/program future sensitivity. Therefore, the objective of this study was 2-fold: (1) to determine whether maternal ENM exposure alters uterine and/or fetal microvascular function and (2) test the Barker hypothesis at the microvascular level. STUDY DESIGN: Pregnant (gestation day 10) Sprague-Dawley rats were exposed to nano-titanium dioxide aerosols (11.3 ± 0.039 mg/m(3)/hr, 5 hr/d, 8.2 ± 0.85 days) to evaluate the maternal and fetal microvascular consequences of maternal exposure. Microvascular tissue isolation (gestation day 20) and arteriolar reactivity studies (<150 µm passive diameter) of the uterine premyometrial and fetal tail arteries were conducted. RESULTS: ENM exposures led to significant maternal and fetal microvascular dysfunction, which was seen as robustly compromised endothelium-dependent and -independent reactivity to pharmacologic and mechanical stimuli. Isolated maternal uterine arteriolar reactivity was consistent with a metabolically impaired profile and hostile gestational environment that impacted fetal weight. The fetal microvessels that were isolated from exposed dams demonstrated significant impairments to signals of vasodilation specific to mechanistic signaling and shear stress. CONCLUSION: To our knowledge, this is the first report to provide evidence that maternal ENM inhalation is capable of influencing fetal health and that the Barker hypothesis is applicable at the microvascular level.

Endothelial caveolar subcellular domain regulation of endothelial nitric oxide synthase.

Complex regulatory processes alter the activity of endothelial nitric oxide synthase (eNOS) leading to nitric oxide (NO) production by endothelial cells under various physiological states. These complex processes require specific subcellular eNOS partitioning between plasma membrane caveolar domains and non-caveolar compartments. Translocation of eNOS from the plasma membrane to intracellular compartments is important for eNOS activation and subsequent NO biosynthesis. We present data reviewing and interpreting information regarding: (i) the coupling of endothelial plasma membrane receptor systems in the caveolar structure relative to eNOS trafficking; (ii) how eNOS trafficking relates to specific protein-protein interactions for inactivation and activation of eNOS; and (iii) how these complex mechanisms confer specific subcellular location relative to eNOS multisite phosphorylation and signalling. Dysfunction in the regulation of eNOS activation may contribute to several disease states, in particular gestational endothelial abnormalities (pre-eclampsia, gestational diabetes etc.), that have life-long deleterious health consequences that predispose the offspring to develop hypertensive disease, Type 2 diabetes and adiposity.