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

ABSTRACT: 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??g 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.

SUBMITTER: Disdier C

PROVIDER: S-EPMC7257152 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Disdier Clémence C Awa Fares F Chen Xiaodi X Dhillon Simerdeep K SK Galinsky Robert R Davidson Joanne O JO Lear Christopher A CA Bennet Laura L Gunn Alistair J AJ Stonestreet Barbara S BS

Journal of neuroinflammation 20200528 1

<h4>Background</h4>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.<h4>Methods</h4>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 μ ...[more]

PMID: 32466771

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Project description:BackgroundThe monocarboxylate transporter 8 (MCT8) plays a vital role in maintaining brain thyroid hormone homeostasis. This transmembrane transporter is expressed at the brain barriers, as the blood-brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene (SLC16A2) cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders. The underlying pathophysiological mechanisms of AHDS remain unclear, and no effective treatments are available for the neurological symptoms of the disease.MethodsNeurovascular unit ultrastructure was studied by means of transmission electron microscopy. BBB permeability and integrity were evaluated by immunohistochemistry, non-permeable dye infiltration assays and histological staining techniques. Brain blood-vessel density was evaluated by immunofluorescence and magnetic resonance angiography. Finally, angiogenic-related factors expression was evaluated by qRT-PCR. The studies were carried out both in an MCT8 deficient subject and Mct8/Dio2KO mice, an AHDS murine model, and their respective controls.ResultsUltrastructural analysis of the BBB of Mct8/Dio2KO mice revealed significant alterations in neurovascular unit integrity and increased transcytotic flux. We also found functional alterations in the BBB permeability, as shown by an increased presence of peripheral IgG, Sodium Fluorescein and Evans Blue, along with increased brain microhemorrhages. We also observed alterations in the angiogenic process, with reduced blood vessel density in adult mice brain and altered expression of angiogenesis-related factors during brain development. Similarly, AHDS human brain samples showed increased BBB permeability to IgG and decreased blood vessel density.ConclusionsThese findings identify for the first time neurovascular alterations in the MCT8-deficient brain, including a disruption of the integrity of the BBB and alterations in the neurovascular unit ultrastructure as a new pathophysiological mechanism for AHDS. These results open a new field for potential therapeutic targets for the neurological symptoms of these patients and unveils magnetic resonance angiography as a new non-invasive in vivo technique for evaluating the progression of the disease.

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Dataset Information

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

Publications

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

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