|Title:||Aberrant astrocytes impair vascular reactivity in Huntington disease||Authors:||Hsiao, Han-Yun
|Issue Date:||2015||Journal Volume:||78||Journal Issue:||2||Start page/Pages:||178-192||Source:||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. ? 2015 American Neurological Association.
|URI:||https://scholars.lib.ntu.edu.tw/handle/123456789/466735||ISSN:||0364-5134||DOI:||10.1002/ana.24428||SDG/Keyword:||carbogen; desmin; huntingtin; mutant huntingtin protein; unclassified drug; vasculotropin A; Huntington protein, mouse; nerve protein; nuclear protein; vascular endothelial growth factor A, mouse; vasculotropin A; VEGFA protein, human; adult; aged; animal cell; animal experiment; animal model; Article; astrocyte; blood brain barrier; blood oxygenation; blood vessel parameters; blood vessel reactivity; brain pericyte; brain vessel density; cause of death; clinical article; controlled study; enzyme linked immunosorbent assay; female; functional magnetic resonance imaging; functional neuroimaging; human; human cell; Huntington chorea; immunohistochemistry; male; middle aged; mouse; nonhuman; pluripotent stem cell; polyacrylamide gel electrophoresis; priority journal; protein expression; signal transduction; Western blotting; animal; astrocyte; blood vessel; brain; cell culture; Huntington chorea; magnetic resonance angiography; metabolism; nerve cell; nuclear magnetic resonance imaging; pathology; pathophysiology; pericyte; transgenic mouse; vascularization; Adult; Aged; Animals; Astrocytes; Blood Vessels; Brain; Cells, Cultured; Female; Humans; Huntington Disease; Induced Pluripotent Stem Cells; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; Middle Aged; Nerve Tissue Proteins; Neurons; Nuclear Proteins; Pericytes; Vascular Endothelial Growth Factor A
|Appears in Collections:||園藝暨景觀學系|
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