Time Course of Changes in the Neurovascular Unit after Hypoxic-Ischemic Injury in Neonatal Rats.

Exposure to hypoxic-ischemic (HI) insults in newborns can predispose them to severe neurological sequela. The mechanisms underlying HI-related brain injury have not been completely elucidated. The neurovascular unit (NVU) is a composite of structures that protect the brain from the influx of detrimental molecules. Changes in the NVU after HI are important because they could reveal endogenous neuroprotective pathways in the cerebral microvasculature. Furthermore, the time course of changes in the NVU after exposure to HI in the newborn remains to be determined. In this study, we examined the effects of severe HI on the time course of changes in the NVU in neonatal rats. Brains were collected from rats exposed to right carotid artery ligation and 2 h of hypoxia on postnatal day 7 with recovery for 6 or 48 h after exposure to sham treatment (Sham) or HI. The right HI and left hypoxic alone sides of the brains were examined by quantitative immunohistochemistry for vascular density (laminin), pericyte vascular coverage (PDGFRß), astrocyte vascular coverage (GFAP), and claudin-5 expression in the microvasculature of the cerebral cortex, white matter, and hippocampus. HI-related brain injury in neonatal rats was associated with increases in vascular density in the cortex and hippocampus 48 h after HI as well as neurovascular remodeling, including loss of pericyte coverage in the cortex and increases in claudin-5 in the hippocampus 6 h after HI. Astrocyte coverage was not affected by HI injury. The time course of the responses in the different components of the NVU varied after exposure to HI. There were also differential regional responses in the elements of the NVU in response to HI and hypoxia alone.

Lipopolysaccharide-induced changes in the neurovascular unit in the preterm fetal sheep brain.

BACKGROUND: Exposure to inflammation during pregnancy can predispose to brain injury in premature infants. In the present study, we investigated the effects of prolonged exposure to inflammation on the cerebrovasculature of preterm fetal sheep. METHODS: Chronically instrumented fetal sheep at 103-104 days of gestation (full term is ~ 147 days) received continuous low-dose lipopolysaccharide (LPS) infusions (100 ng/kg over 24 h, followed by 250 ng/kg/24 h for 96 h plus boluses of 1 µg LPS at 48, 72, and 96 h) or the same volume of normal saline (0.9%, w/v). Ten days after the start of LPS exposure at 113-114 days of gestation, the sheep were killed, and the fetal brain perfused with formalin in situ. Vessel density, pericyte and astrocyte coverage of the blood vessels, and astrogliosis in the cerebral cortex and white matter were determined using immunohistochemistry. RESULTS: LPS exposure reduced (P < 0.05) microvascular vessel density and pericyte vascular coverage in the cerebral cortex and white matter of preterm fetal sheep, and increased the activation of perivascular astrocytes, but decreased astrocytic vessel coverage in the white matter. CONCLUSIONS: Prolonged exposure to LPS in preterm fetal sheep resulted in decreased vessel density and neurovascular remodeling, suggesting that chronic inflammation adversely affects the neurovascular unit and, therefore, could contribute to long-term impairment of brain development.