Cerebrovascular adaptations to chronic hypoxia in the growth restricted lamb

Abstract

Chronic moderate hypoxia induces angiogenic adaptation in the brain, reflecting a modulatory role for oxygen in determining cerebrovascular development. Chronic intrauterine fetal hypoxia, such as occurs in intrauterine growth restriction (IUGR) is likely to lead to a reduction in oxygen delivery to the brain and long-term neurological abnormalities. Thus we investigated whether vascular remodeling and vascular abnormalities were evident in the brain of IUGR newborn lambs that were chronically hypoxic in utero. Single uterine artery ligation (SUAL) surgery was performed in fetuses at ∼ 105 days gestation (term ∼ 145 days) to induce placental insufficiency and IUGR. Ewes delivered naturally at term and lambs were euthanased 24h later. IUGR brains (n = 9) demonstrated a significant reduction in positive staining for the number of blood vessels (laminin immunohistochemistry) compared with control (n = 8): from 1650 ± 284 to 416 ± 47 cells/mm(2) in subcortical white matter (SCWM) 1793 ± 298 to 385 ± 20 cells/mm(2) in periventricular white matter (PVWM), and 1717 ± 161 to 405 ± 84 cells/mm(2) in the subventricular zone (SVZ). The decrease in vascular density was associated with a significant decrease in VEGF immunoreactivity. The percentage of blood vessels exhibiting endothelial cell proliferation (Ki67 positive) varied regionally between 14 to 22% in white matter of control lambs, while only 1-3% of blood vessels in IUGR brains showed proliferation. A 66% reduction in pericyte coverage (α-SMA and desmin) of blood vessels was observed in SCWM, 71% in PVWM, and 73% in SVZ of IUGR lambs, compared to controls. A reduction in peri-vascular astrocytes (GFAP and laminin) was also observed throughout the white matter of IUGR lambs, and extravasation of albumin into the brain parenchyma was present, indicative of increased permeability of the blood brain barrier. Chronic hypoxia associated with IUGR results in a reduction in vascular density in the white matter of IUGR newborn brains. Vascular pericyte coverage and peri-vascular astrocytes, both of which are essential for stabilisation of blood vessels and the maintenance of vascular permeability, were also decreased in the white matter of IUGR lambs. In turn, these vascular changes could lead to inadequate oxygen supply and contribute to under-perfusion and increased vulnerability of white matter in IUGR infants.

Brain-Sparing in Intrauterine Growth Restriction: Considerations for the Neonatologist

“…Although remodelling may help preserve energy under detrimental intrauterine circumstances, the postnatal implications of these adaptations have not been well investigated. In fact, a recent study demonstrated compromised structural integrity and stability of the cerebral microvasculature in IUGR lambs, increasing the blood-brain barrier permeability and their risk for cerebral haemorrhages [41]. …”

“…Based on these studies it has even been proposed that increased CBF reflects advancing stages of brain injury; not a protective mechanism against it [54,55,57]. As described previously, IUGR may be associated with vascular remodelling and reduced vasoreactivity [18,39,40,41,42]. The increased CBF may in part be a direct consequence of disturbed circulatory regulation.…”

“…A study by Alderliesten et al [75 ]has shown that preterm neonates who develop severe peri-intraventricular haemorrhage show signs of cerebral hyperperfusion and suboptimal cerebral autoregulation. Thus, postnatal continuation of increased CBF [46,47] in combination with potential loss of cerebral autoregulation [18,65] and increased blood-brain barrier permeability [41] could make the preterm IUGR brain especially vulnerable to haemorrhagic insults. In fact, a sheep model of IUGR demonstrated highly reduced perivascular astrocytes and pericyte coverage of the microvasculature in several brain regions, including the germinal matrix [41].…”

“…Thus, postnatal continuation of increased CBF [46,47] in combination with potential loss of cerebral autoregulation [18,65] and increased blood-brain barrier permeability [41] could make the preterm IUGR brain especially vulnerable to haemorrhagic insults. In fact, a sheep model of IUGR demonstrated highly reduced perivascular astrocytes and pericyte coverage of the microvasculature in several brain regions, including the germinal matrix [41]. These histologic changes are believed to result in decreased stability of the cerebral microvasculature and are linked to ICH [41,76].…”

Reduction in Cerebral Oxygenation due to Patent Ductus Arteriosus Is Pronounced in Small-for-Gestational-Age Neonates

“…New insights suggest that chronic intrauterine hypoxia results in cerebrovascular remodelling [17], which may limit the cerebral autoregulatory response to hypoperfusion [6]. In fact, our SGA-hsPDA neonates demonstrated similar MABP, pulse pressure and SpO 2 to AGA-hsPDA neonates.…”