Hypoxic regulation of the fetal cerebral circulation

Abstract

Fetal cerebrovascular responses to acute hypoxia are fundamentally different from those observed in the adult cerebral circulation. The magnitude of hypoxic vasodilatation in the fetal brain increases with postnatal age although fetal cerebrovascular responses to acute hypoxia can be complicated by age-dependent depressions of blood pressure and ventilation. Acute hypoxia promotes adenosine release, which depresses fetal cerebral oxygen consumption through action of adenosine on neuronal A1 receptors and vasodilatation through activation of A2 receptors on cerebral arteries. The vascular effect of adenosine can account for approximately half the vasodilatation observed in response to hypoxia. Hypoxia-induced release of nitric oxide and opioids can account for much of the adenosine-independent cerebral vasodilatation observed in response to hypoxia in the fetus. Direct effects of hypoxia on cerebral arteries account for the remaining fraction, although the vascular endothelium contributes relatively little to hypoxic vasodilatation in the immature cerebral circulation. In contrast to acute hypoxia, fetal cerebral blood flow tends to normalize during acclimatization to chronic hypoxia even though cardiac output is depressed. However, uncompensated chronic hypoxia in the fetus can produce significant changes in brain structure and function, alteration of respiratory drive and fluid balance, and increased incidence of intracranial hemorrhage and periventricular leukomalacia. At the level of the fetal cerebral arteries, chronic hypoxia increases protein content and depresses norepinephrine release, contractility, and receptor densities associated with contraction but also attenuates endothelial vasodilator capacity and decreases the ability of ATP-sensitive and calcium-sensitive potassium channels to promote vasorelaxation. Overall, fetal cerebrovascular adaptations to chronic hypoxia appear prioritized to conserve energy while preserving basic contractility. Many gaps remain in our understanding of how the effects of acute and chronic hypoxia are mediated in fetal cerebral arteries, but studies of adult cerebral arteries have produced many powerful pharmacological and molecular tools that are simply awaiting application in studies of fetal cerebral artery responses to hypoxia.

Intracerebral regional distribution of blood flow in response to uterine contractions in growth-restricted human fetuses

“…In congruence with the present findings, animal studies have shown spatial and temporal homogeneity of flow changes in cerebral cortex areas in response to induced 14 acute hypoxia, and the homogeneity increases during hypoxia 19 . However, evidence of preferential flow changes exists in other structures of the central nervous system: hypoxia-induced vasodilatation is most robust in the brain stem, and the brain stem is more resistant to hypoxic injury than other brain areas 20 .…”

Effects of binge alcohol exposure in the second trimester on intracerebral arteriolar function in third trimester fetal sheep

“…Because cerebrovascular hypoxic vasodilation is mediated, in part, by adenosine (Blood et al, 2003;Morii et al, 1987;Pearce, 2006), we hypothesized that alcohol exposure might affect vasodilatory responses of cerebral vessels to adenosine. Instead, the present findings reveal that alcohol exposure did not alter the response of fetal sheep cerebral arterioles to endogenous vasoactive mediators, including adenosine.…”

“…However, chronic alcohol exposure has well known adverse effects on brain blood vessels (Daft et al, 1986;Turcotte et al, 2002;Vorbrodt et al, 2001). Because of the overall importance of cerebrovascular regulation in brain function and development (Iadecola, 2004;Pearce, 2006), the deleterious vascular effects of alcohol may contribute to the wide range of neuropathology reported in individuals exposed to alcohol prenatally.…”

“…We have developed a sheep model of binge fetal alcohol exposure and previously reported that early fetal alcohol exposure is associated with later attenuation of cerebral blood flow (CBF) responses to hypoxia in both fetuses (Mayock et al, 2007) and newborns (Gleason et al, 1997). Cerebrovascular hypoxic vasodilation is believed to be mediated, in part, by adenosine (Blood et al, 2003;Morii et al, 1987;Pearce, 2006). Its actions are mediated by specific cell surface receptors coupled to G-proteins, including A 1 , A 2A , A 2B and A 3 subtypes (Fredholm et al, 2001).…”

Brain Injury in Preterm Infants

“…However, the exact degree of hypoxia that leads to irreversible brain damage has not as yet been determined. The fetal brain has the ability to react in hypoxia by increasing the cerebral blood flow via reflex vasodilatation (Pearce 2006). Moreover, always to be borne in mind is the anatomical vulnerability and relative vulnerability of different areas and populations of oligodendronglia in white matter.…”