Nuyt AM. Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet. Am J Physiol Regul Integr Comp Physiol 292: R1236 -R1245, 2007. First published November 30, 2006; doi:10.1152/ajpregu.00227.2006.-Developmental programming of hypertension is associated with vascular dysfunction characterized by impaired vasodilatation to nitric oxide, exaggerated vasoconstriction to ANG II, and microvascular rarefaction appearing in the neonatal period. Hypertensive adults have indices of increased oxidative stress, and newborns that were nutrient depleted during fetal life have decreased antioxidant defenses and increased susceptibility to oxidant injury. To test the hypothesis that oxidative stress participates in early life programming of hypertension, vascular dysfunction, and microvascular rarefaction associated with maternal protein deprivation, pregnant rats were fed a normal, low protein (LP), or LP plus lazaroid (lipid peroxidation inhibitor) isocaloric diet from the day of conception until delivery. Lazaroid administered along with the LP diet prevented blood pressure elevation, enhanced vasomotor response to ANG II, impaired vasodilatation to sodium nitroprusside, and microvascular rarefaction in adult offspring. Liver total glutathione was significantly decreased in LP fetuses, and kidney eight-isoprostaglandin F2␣ (8-isoPGF 2␣) levels were significantly increased in adult LP offspring; these modifications were prevented by lazaroid. Renal nitrotyrosine abundance and blood levels of 1,4-dihydroxynonene and 4-hydroxynonenal-protein adducts were not modified by antenatal diet exposure. This study shows in adult offspring of LP-fed dams prevention of hypertension, vascular dysfunction, microvascular rarefaction, and of an increase in indices of oxidative stress by the administration of lazaroid during gestation. Lazaroid also prevented the decrease in antioxidant glutathione levels in fetuses, suggesting an antenatal mild oxidative stress in offspring of LP-fed dams. These studies support the concept that perinatal oxidative insult can lead to permanent alterations in the cardiovascular system development.hypertension; vascular dysfunction; developmental origin of adult disease; oxidative stress; antioxidants.Cardiovascular diseases represent currently the leading cause of mortality in Western countries. The hypothesis of a developmental origin of these pathologies derives from epidemiological studies, indicating that, independent of genetic or life style factors, the risks of hypertension (HT), stroke, and coronary heart disease in later life are inversely proportional to birth weight. Alteration of the vascular response to ACh, a decreased arterial compliance, and an increased incidence of atherosclerosis are all evidence further illustrating the vascular risk in children and adults born with low birth weight and/or intrauterine growth retardation (3,4,44,47).Experimentally, HT is observed in adults after malnutrit...

Abstract-Long-term vascular and renal consequences of neonatal oxidative injury are unknown. Using a rat model, we sought to investigate whether vascular function and blood pressure are altered in adult rats exposed to hyperoxic conditions as neonates. We also questioned whether neonatal O 2 injury causes long-term renal damage, important in the pathogenesis of hypertension. Sprague-Dawley pups were kept with their mother in 80% O 2 or room air from days 3 to 10 postnatal, and blood pressure was measured (tail cuff) from weeks 7 to 15. Rats were euthanized, and vascular reactivity (ex vivo carotid rings), oxidative stress (lucigenin chemiluminescence and dihydroethidium fluorescence), microvascular density (tibialis anterior muscle), and nephron count were studied. In male and female rats exposed to O 2 as newborns, systolic and diastolic blood pressures were increased (by an average of 15 mm Hg); ex vivo, maximal vasoconstriction (both genders) and sensitivity (males only) specific to angiotensin II were increased; endotheliumdependant vasodilatation to carbachol but not to NO-donor sodium nitroprussiate was impaired; superoxide dismutase analogue prevented vascular dysfunction to angiotensin II and carbachol; vascular superoxide production was higher; and capillary density (by 30%) and number of nephrons per kidney (by 25%) were decreased. These data suggest that neonatal hyperoxia leads in the adult rat to increased blood pressure, vascular dysfunction, microvascular rarefaction, and reduced nephron number in both genders. Our findings support the hypothesis of developmental programming of adult cardiovascular and renal diseases and provide new insights into the potential role of oxidative stress in this process. Key Words: hypertension Ⅲ vascular dysfunction Ⅲ developmental origin of adult onset disease Ⅲ oxygen Ⅲ angiotensin Ⅲ microvascular rarefaction Ⅲ nephron number P remature babies, representing Ϸ8% of all births, have decreased antioxidant defenses and are exposed on birth to high oxygen (O 2 ) concentration relative to the intrauterine milieu. 1,2 This results in high O 2 -derived free radicals. Evidence in humans and animal studies indicate that premature newborns are more susceptible to oxidative tissue damage, leading to pathologies such as retinopathy of prematurity and bronchopulmonary dysplasia. 3,4 However, the long-term vascular and blood pressure consequences of neonatal hyperoxic injury are unknown.It is becoming increasingly evident that conditions early in life can influence adult diseases; however, the mechanisms are incompletely understood. 5,6 Recent data suggest that perinatal oxidative stress may be the initiating trigger in long-term programming of cardiovascular function. In a previous study, we found that cellular antioxidant glutathione is decreased in the fetus of dams fed a low-protein (LP) diet during gestation. In that model, administration of the peroxidation inhibitor lazaroid to the pregnant dam prevented elevated blood pressure, vascular dysfunction, and microvascular rar...

Purpose of review There is a growing body of evidence linking adverse events or exposures during early life and adult-onset diseases. After important epidemiological studies from many parts of the world, research now focuses on mechanisms of organ dysfunction and on refining the understanding of the interaction between common elements of adverse perinatal conditions, such as nutrition, oxidants, and toxins exposures. This review will focus on advances in our comprehension of developmental programming of hypertension. Recent findings Recent studies have unraveled important mechanisms of oligonephronia and impaired renal function, altered vascular function and structure as well as sympathetic regulation of the cardiovascular system. Furthermore, interactions between prenatal insults and postnatal conditions are the subject of intensive research. Prematurity vs. intrauterine growth restriction modulate differently programming of high blood pressure. Along with antenatal exposure to glucocorticoids and imbalanced nutrition, a critical role for perinatal oxidative stress is emerging. Summary While the complexity of the interactions between antenatal and postnatal influences on adult blood pressure is increasingly recognized, the importance of postnatal life in (positively) modulating developmental programming offers the hope of a critical window of opportunity to reverse programming and prevent or reduce related adult-onset diseases.

Cardiovascular-related diseases are the leading cause of death in the world in both men and women. In addition to the environmental and genetic factors, early life conditions are now also considered important contributing elements to these pathologies. The concept of 'fetal' or 'developmental' origins of adult diseases has received increased recognition over the last decade, yet the mechanism by which altered perinatal environment can lead to dysfunction mostly apparent in the adult are incompletely understood. This review will focus on the mechanisms and pathways that epidemiological studies and experimental models have revealed underlying the adult cardiovascular phenotype dictated by the perinatal experience, as well as the probable key causal or triggering elements. Programmed elevated blood pressure in the adult human or animal is characterized by vascular dysfunction and microvascular rarefaction. Developmental mechanisms that have been more extensively studied include glucocorticoid exposure, the role of the kidneys and the renin-angiotensin system. Other pathophysiological pathways have been explored, such as the role of the brain and the sympathetic nervous system, oxidative stress and epigenetic changes. As with many complex diseases, a unifying hypothesis linking the perinatal environment to elevated blood pressure and vascular dysfunction in later life cannot be presumed, and a better understanding of those mechanisms is critical before clinical trials of preventive or 'deprogramming' measures can be designed.

Intrauterine programming of hypertension is associated with evidence of increased renin-angiotensin system (RAS) activity. The current study was undertaken to investigate whether arterial baroreflex and blood pressure variability are altered in a model of in utero programming of hypertension secondary to isocaloric protein deprivation and whether activation of the RAS plays a role in this alteration. Pregnant Wistar rats were fed a normalprotein (18%) or low-protein (9%) diet during gestation, which had no effect on litter size, birth weight, or pup survival. Mean arterial blood pressure (MABP; 126 Ϯ 3 mm Hg 9% versus 108 Ϯ 4 mm Hg 18%; p Ͻ 0.05) and blood pressure variability were significantly greater in the adult offspring of the 9% protein-fed mothers. Arterial baroreflex control of heart rate, generated by graded i.v. infusion of phenylephrine and nitroprusside, was significantly shifted toward higher pressure; i.v. angiotensinconverting enzyme inhibitor normalized MABP and shifted the arterial baroreflex curve of the 9% offspring toward lower pressure without affecting the 18% offspring. For examining whether brain RAS is also involved in programming of hypertension, angiotensin-converting enzyme inhibitor and losartan (specific AT 1 receptor antagonist) were administered intracerebroventricularly; both significantly reduced MABP of the 9% but not the 18% offspring. Autoradiographic receptor binding studies demonstrated an increase in brain AT 1 expression in the subfornical organ and the vascular organ of the lamina terminalis in the 9% offspring. These data demonstrate a major tonic role of brain and peripheral RAS on hypertension associated with antenatal nutrient deprivation. Abbreviations ACE-I, angiotensin-converting enzyme inhibitor AngII, angiotensin II AP, area postrema BPV, blood pressure variability HR, heart rate ICV, intracerebroventricular MABP, mean arterial blood pressure MEPO, median preoptic nucleus NTS, nucleus of the solitary tract OVLT, vascular organ of the lamina terminalis PVH, paraventricular nucleus of the hypothalamus RAS, renin-angiotensin system SFO, subfornical organ Chronic cardiovascular diseases of adults can have their origins in fetal life. Epidemiologic studies reveal that hypertension, stroke, and coronary heart disease are inversely related to birth weight (1) and that this relationship is independent of genetic factors (2) and lifestyle (3). It has been suggested that a poor nutrient supply at a critical period of early development leads to permanent alterations in the programming of the developing cardiovascular structures or functions (4). This concept has been supported by animal studies demonstrating an association between nutritional deficit during fetal life and increased blood pressure in adulthood (5, 6).Experimental evidence suggests that activation of the reninangiotensin system (RAS) (7,8) is an important element of hypertension programmed during fetal life. Infants who are born with intrauterine growth restriction have increased plasma renin activity and r...

Key Points Question Is vitamin D supplementation during pregnancy beneficial and safe for offspring? Findings In this systematic review and meta-analysis of 24 randomized clinical trials including 5405 individuals, vitamin D supplementation during pregnancy was associated with a lower risk of infants being small for gestational age and improved growth during infancy without an increased risk of fetal or neonatal mortality or congenital abnormality. Meaning Vitamin D supplementation during pregnancy may reduce the risk of infants being small for gestational age and improve growth during infancy without an increased risk of fetal or neonatal mortality or congenital abnormality.

In hypertension, increased peripheral vascular resistance results from vascular dysfunction with or without structural changes (vessel wall remodeling and/or microvascular rarefaction). Humans with lower birth weight exhibit evidence of vascular dysfunction. The current studies were undertaken to investigate whether in utero programming of hypertension is associated with in vivo altered response and/or abnormal vascular structure. Offspring of Wistar dams fed a normal (CTRL) or low (LP)-protein diet during gestation were studied. Mean arterial blood pressure response to ANG II was significantly increased, and depressor response to sodium nitroprusside (SNP) infusions significantly decreased in male LP adult offspring relative to CTRL. No arterial remodeling was observed in male LP compared with CTRL offspring. Capillary and arteriolar density was significantly decreased in striated muscles from LP offspring at 7 and 28 days of life but was not different in late fetal life [day 21 of gestation (E21)]. Angiogenic potential of aortic rings from LP newborn (day of birth, P0) was significantly decreased. Striated muscle expressions (Western blots) of ANG II AT(1) receptor subtype, endothelial nitric oxide synthase, angiopoietin 1 and 2, Tie 2 receptor, vascular endothelial growth factor and receptor, and platelet-derived growth factor C at E21 and P7 were unaltered by antenatal diet exposure. In conclusion, blood pressure responses to ANG II and SNP are altered, and microvascular structural changes prevail in this model of fetal programming of hypertension. The capillary rarefaction is absent in the fetus and appears in the neonatal period, in association with decreased angiogenic potential. The study suggests that intrauterine protein restriction increases susceptibility to postnatal factors resulting in microvascular rarefaction, which could represent a primary event in the genesis of hypertension.

Background Prematurely born infants are highly vulnerable to infections and also exhibit a high susceptibility to organ damage from inflammation. Methods To investigate homeostatic immune control early in life, we used advanced multi-parameter flow cytometry to compare responses to multiple Toll-like receptor (TLR) ligands in single cells and mononuclear cell populations, between term and preterm neonates born before 29 weeks of gestation. Results Preterm neonates showed globally attenuated TLR-stimulated IL-6, IFN-α and to a lesser extent TNF-α responses, but relative preservation of anti-inflammatory IL-10 responses in monocytes and dendritic cell subtypes. Remarkably, preterm neonates were also profoundly deficient in the common IL-12 and IL-23 cytokines p40 subunit, critical for immunity against a wide variety of microbial pathogens in mice. Consistent with an increased susceptibility to infections from the lack of IL-12/IL-23 in human newborns, significantly lower serum p40 concentrations were observed at birth in infants who developed early-onset sepsis. Conclusion This study is the first detailed analysis of multiple TLR function in neonates born at extreme prematurity. While attenuation of pro-inflammatory pathways may protect against tissue-damaging immunity early in life, this previously unrecognized p40 immune deficiency appears to considerably increase susceptibility to infection in human preterm newborns.