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 F2α (8-isoPGF_2α) 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.

In the epidemiologic context of maternal obesity and type 2 diabetes (T2D), the incidence of gestational diabetes has significantly increased in the last decades. Infants of diabetic mothers are prone to various neonatal adverse outcomes, including metabolic and hematologic disorders, respiratory distress, cardiac disorders and neurologic impairment due to perinatal asphyxia and birth traumas, among others. Macrosomia is the most constant consequence of diabetes and its severity is mainly influenced by maternal blood glucose level. Neonatal hypoglycemia is the main metabolic disorder that should be prevented as soon as possible after birth. The severity of macrosomia and the maternal health condition have a strong impact on the frequency and the severity of adverse neonatal outcomes. Pregestational T2D and maternal obesity significantly increase the risk of perinatal death and birth defects. The high incidence of maternal hyperglycemia in developing countries, associated with the scarcity of maternal and neonatal care, seriously increase the burden of neonatal complications in these countries.

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; endothelium-dependant 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.

Individuals born after intrauterine growth restriction (IUGR) have an increased risk of perinatal morbidity/mortality, and those who survive face long-term consequences such as cardiovascular-related diseases, including systemic hypertension, atherosclerosis, coronary heart disease and chronic kidney disease. In addition to the demonstrated long-term effects of decreased nephron endowment and hyperactivity of the hypothalamic–pituitary–adrenal axis, individuals born after IUGR also exhibit early alterations in vascular structure and function, which have been identified as key factors of the development of cardiovascular-related diseases. The endothelium plays a major role in maintaining vascular function and homeostasis. Therefore, it is not surprising that impaired endothelial function can lead to the long-term development of vascular-related diseases. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation and vascular remodeling, involves decreased nitric oxide (NO) bioavailability, impaired endothelial NO synthase functionality, increased oxidative stress, endothelial progenitor cells dysfunction and accelerated vascular senescence. Preventive approaches such as breastfeeding, supplementation with folate, vitamins, antioxidants, L-citrulline, L-arginine and treatment with NO modulators represent promising strategies for improving endothelial function, mitigating long-term outcomes and possibly preventing IUGR of vascular origin. Moreover, the identification of early biomarkers of endothelial dysfunction, especially epigenetic biomarkers, could allow early screening and follow-up of individuals at risk of developing cardiovascular and renal diseases, thus contributing to the development of preventive and therapeutic strategies to avert the long-term effects of endothelial dysfunction in infants born after IUGR.