Circulatory and metabolic effect of anemia in hyperinsulinemic ovine fetuses

Infants born to women with poorly controlled diabetes mellitus have an increased incidence of perinatal asphyxia, cardiovascular abnormalities, elevated catecholamines, and sudden fetal death. Although hyperinsulinemic fetuses of diabetic women often exhibit polycythemia, they may also develop anemia because of pregnancy- and/or delivery-related complications. Experimental fetal hyperinsulinemia results in cardiovascular changes and a surge in catecholamines. We hypothesized that reductions in fetal O2 availability via anemic hypoxia limits O2 transport and compromises the hemodynamically and metabolically stressed but compensated hyperinsulinemic fetus. Chronically catheterized fetuses receiving insulin (n = 9) or placebo (n = 5) for 48 h were rendered anemic by an isovolemic exchange transfusion. In the hyperinsulinemic state, anemic-hypoxia augmented the insulin-mediated surge in norepinephrine concentration and increases in blood flow to brain, heart, and adrenal glands. Insulin-related increase in the combined ventricular output was sustained during anemia. O2 delivery to the fetus decreased, extraction increased, and O2 uptake did not change. Regional O2 delivery to the brain, kidney, gastrointestinal tract, muscle, fat, pancreas, spleen, and carcass decreased. Hyperinsulinemic ovine fetus exposed to anemic hypoxia demonstrated an accentuated surge in norepinephrine, a sustained increase in the combined ventricular output, preservation of systemic O2 uptake, and compromised regional O2 delivery to certain vascular regions. We conclude that the hyperinsulinemic fetus was able to compensate for anemic hypoxia by increased or sustained regional vascular perfusion

Development of the blood-brain barrier: relationship to perinatal medicine

The blood-brain barrier maintains central nervous system homeostasis and limits the entry of blood-borne substances that could alter neuronal function and survival. The barrier exists predominantly at the endothelium of cerebral vascular microvessels. The cerebral vascular endothelium becomes highly specialized during the formation of the neurovascular unit early in embryonic development. The blood-brain barrier is present and functional early in fetal life. The tightness of the barrier gradually increases throughout gestation and in the newborn period. Alterations in the basolateral environment of the cerebral microvasculature can modify the blood-brain barrier properties by modulating the expression of the endothelial tight junctions and other biochemical properties of the cerebral vascular endothelium. Maturation of the blood-brain barrier late in gestation correlates with increases in endogenous corticosteroids and with exposure to exogenous corticosteroids. Several adverse fetal and neonatal conditions can alter the structure and function of the blood-brain barrier. Impairment of blood-brain barrier function in the perinatal period could increase the entry of bilirubin and other neurotoxic substances from the systemic circulation into the brain, thereby exacerbating and/or causing damage to the developing brain

Ischemia-reperfusion injury in the intestines of newborn pigs

Although the pathogenesis of necrotizing enterocolitis remains uncertain, ischemia appears to be an important contributing factor to the development of this disorder. Reperfusion plays a major role in ischemia- related injury, and oxygen free radicals produced during reperfusion most likely contribute to the injury. These oxidants can be generated during prostanoid metabolism, which increases during reperfusion of ischemic gut in adult subjects. The present study was designed to: 1) examine the effects of superior mesenteric artery occlusion, e.g. ischemia and reperfusion in vivo on the development of histopathologic intestinal injury; 2) determine whether products of arachidonic acid metabolism, e.g. prostanoids are increased during reperfusion of ischemic gut; and 3) determine whether oxygen free radical scavengers attenuate the injury in newborn pigs. Chronically catheterized placebo-pretreated newborn pigs exposed to ischemia-reperfusion, placebo-pretreated nonischemic control pigs, and polyethylene glycol- superoxide dismutase (SOD) plus polyethylene glycol-catalase (CAT)- pretreated, ischemic pigs were studied by examining changes in intestinal circulation, oxygenation, prostanoids, and tissue injury. In the placebo- pretreated pigs, intestinal blood flow decreased to very low levels during superior mesenteric artery occlusion. During reperfusion, blood flow increased, but remained below baseline. After ischemia, oxygen uptake returned to values that were similar to baseline. Intestinal efflux of the vasodilator 6-keto-prostaglandin F(1α) was evident (p < 0.05 versus no or zero efflux) during early reperfusion. Histopathologic scoring of terminal ileal samples showed significant mucosal necrosis, surface epithelial disruption, lamina propria congestion and hemorrhage, submucosal hemorrhage, edema, and increases in cells compared with the placebo-pretreated nonischemic pigs. In the SOD plus CAT-pretreated ischemic pigs, changes in intestinal blood flow, oxygen uptake, 6-keto-prostaglandin F(1α) efflux, and the pattern of the ileal tissue injury did not differ significantly from the placebo-pretreated ischemic pigs. In summary, superior mesenteric artery occlusion for 1 h and reperfusion for 2 h resulted in severe intestinal ischemia, early postocclusive limited increases in intestinal perfusion and oxygen uptake, efflux of vasodilating prostanoids during early reperfusion, and signs of ischemic tissue injury in the placebo- and SOD plus CAT- pretreated pigs. This study demonstrates that, after superior mesenteric artery occlusion and reperfusion, severe intestinal tissue injury is detected in vivo, prostanoid efflux increases, and SOD plus CAT given just before occlusion does not attenuate the extent of injury in newborn pigs

Brain organoids for hypoxic-ischemic studies: from bench to bedside

Our current knowledge regarding the development of the human brain mostly derives from experimental studies on non-human primates, sheep, and rodents. However, these studies may not completely simulate all the features of human brain development as a result of species differences and variations in pre- and postnatal brain maturation. Therefore, it is important to supplement the in vivo animal models to increase the possibility that preclinical studies have appropriate relevance for potential future human trials. Three-dimensional brain organoid culture technology could complement in vivo animal studies to enhance the translatability of the preclinical animal studies and the understanding of brain-related disorders. In this review, we focus on the development of a model of hypoxic-ischemic (HI) brain injury using human brain organoids to complement the translation from animal experiments to human pathophysiology. We also discuss how the development of these tools provides potential opportunities to study fundamental aspects of the pathophysiology of HI-related brain injury including differences in the responses between males and females

Ischemia/Reperfusion-induced neovascularization in the cerebral cortex of the ovine fetus.

Information is limited regarding the effects of injury on neovascularization in the immature brain.We investigated effects of ischemia on cerebral cortical neovascularization after exposure of fetuses to 30 minutes of cerebral ischemia and 48- (I/R-48) or 72- (I/R-72) hours of reperfusion or sham-control treatment (Non-I/R). Immunohistochemical and morphometric analyses of cerebral cortical sections included immunostaining for glial fibrillary acidic protein and collagen type IV (Coll IV), a molecular component of the vascular basal lamina, to determine the glial-vascular network in fetal brains, and Ki67 as a proliferation marker. Cerebral cortices from I/R-48 and I/R-72 fetuses exhibited general responses to ischemia, including reactive astrocyte morphology, which was not observed in Non-I/R fetuses. Cell bodies of reactive, proliferating astrocytes along with large end-feet surrounded walls of cerebral cortical microvessels in addition to the thick Coll IV-enriched basal lamina. Morphometric analysis of Non-I/R with I/R-48 and I/R-72 groups revealed increased Coll IV density in I/R-72 cerebral cortical microvessels (p < 0.01), which also frequently displayed a sprouting appearance, characterized by growing tip cells and activated pericytes. Increases in cerebral cortical basic fibroblast growth factor were associated with neovascularization. We conclude that increased neovascularization occurs within 72 hours after ischemia in fetal cerebral cortices