Cited by 99Genetic Neurodegenerative DiseasesBarrier Structure and Function StudiesNeurological Disease Mechanisms and Treatments

Aberrant astrocytes impair vascular reactivity in H untington disease

Hsiao, Han‐Yun, Chen, Yu‐Chen, Huang, Chien‐Hsiang, Chen, Chiao‐Chi, Hsu, Yi‐Hua, Chen, Hui‐Mei, Chiu, Feng‐Lan, Kuo, Hung‐Chih +2 more·2015·Annals of Neurology

Abstract

OBJECTIVE: Huntington disease (HD) is an inherited neurodegenerative disease caused by the mutant huntingtin gene (mHTT), which harbors expanded CAG repeats. We previously reported that the brain vessel density is higher in mice and patients with HD than in controls. The present study determines whether vascular function is altered in HD and characterizes the underlying mechanism. METHODS: The brain vessel density and vascular reactivity (VR) to carbogen challenge of HD mice were monitored by 3D ΔR2 -mMRA and blood oxygenation level-dependent (BOLD)/flow-sensitive alternating inversion recovery (FAIR) magnetic resonance imaging (MRI), respectively. The amount of vascular endothelial growth factor (VEGF)-A and the pericyte coverage were determined by immunohistochemistry and enzyme-linked immunosorbent assay in human and mouse brain sections, primary mouse astrocytes and pericytes, and human astrocytes derived from induced pluripotent stem cells. RESULTS: Expression of mHTT in astrocytes and neurons is sufficient to increase the brain vessel density in HD mice. BOLD and FAIR MRI revealed gradually impaired VR to carbogen in HD mice. Astrocytes from HD mice and patients contained more VEGF-A, which triggers proliferation of endothelial cells and may be responsible for the augmented neurovascular changes. Moreover, an astrocytic inflammatory response, which reduces the survival of pericytes through an IκB kinase-dependent pathway, mediates the low pericyte coverage of blood vessels in HD brains. INTERPRETATION: Our findings suggest that the inflammation-prone HD astrocytes provide less pericyte coverage by promoting angiogenesis and reducing the number of pericytes and that these changes can explain the inferior VR in HD mice. The resultant impaired VR might hinder cerebral hemodynamics and increase brain atrophy during HD progression.

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Crossref · 10.1002/ana.24428

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  • Histological analysis of BBB breakdown shows perivascular capillary fibrin(ogen) deposition, diminished endothelial tight junction proteins claudin-5 and occludin, and reduced pericyte coverage in HD brains.

    “Histological analysis of BBB breakdown shows perivascular capillary fibrin(ogen) deposition, diminished endothelial tight junction proteins claudin-5 and occludin (155), and reduced pericyte coverage (263) in HD brains.”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [263]

  • BBB dysfunction is evident in HD.

    “Although not often associated with HD pathophysiology, BBB dysfunction is evident in HD (155, 263, 364).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [263]

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Authors
Hsiao, H., Chen, Y., Huang, C., Chen, C., Hsu, Y., Chen, H., Chiu, F., Kuo, H., Chang, C., & Chern, Y.
Affiliations
  • Institute of Biomedical Sciences, Academia Sinica (TW)
  • National Taiwan University (TW)
  • Institute of Cellular and Organismic Biology, Academia Sinica (TW)
Corresponding author
  • Chang, Chen
  • Chern, Yijuang
Venue
Annals of Neurology
Publisher
Wiley
Published
2015-06-30
Volume
78
Issue
2
Pages
178-192
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
OpenAlex
W1480691962
Cited by
99
References
45
Citations by year
2026: 9 · 2025: 5 · 2024: 9 · 2023: 6 · 2022: 11 · 2021: 9 · 2020: 8 · 2019: 12 · 2018: 13 · 2017: 8 · 2016: 4 · 2015: 5
FWCI
4.67
Type
journal article
Language
en
Open access
closed
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Council Taiwan (NSC97-2321-B-001-030, NSC98-2321-B-001-017, NSC99-2321-B-001-012, NSC100-2321-B-001-009, NSC101-2321-B-001-047, 102-2321-B-001-062, 100-2319-B-001-003-m, 99-3112-B-001-020)
  • Academia Sinica (AS-100-TP2-B02)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Huntington's disease, mutant huntingtin, astrocytes, vascular reactivity, VEGF-A, angiogenesis, pericyte coverage, cerebral hemodynamics, neurovascular dysfunction
MeSH terms
Huntingtin Protein, Adult, Aged, Animals, Astrocytes, Blood Vessels, Brain, Cells, Cultured, Female, Humans, Huntington Disease, Magnetic Resonance Imaging, Male, Mice, Transgenic, Middle Aged, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Magnetic Resonance Angiography, Pericytes, Vascular Endothelial Growth Factor A, Mice, Induced Pluripotent Stem Cells

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