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Updated: Apr 14, 2026
Monitoring Astrocyte Reactivity and Proliferation in Vitro Under Ischemic-Like Conditions
Published on: October 21, 2017
Aberrant astrocytes impair vascular reactivity in Huntington disease
Han-Yun Hsiao1,2, Yu-Chen Chen1,2, Chien-Hsiang Huang1,3
1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Insights
Huntington disease (HD) astrocytes promote abnormal blood vessel growth and reduced pericyte coverage, impairing brain vascular function and potentially worsening atrophy.
Area of Science:
- Neuroscience
- Genetics
- Vascular Biology
Background:
- Huntington disease (HD) is a neurodegenerative disorder caused by the mutant huntingtin gene (mHTT) with expanded CAG repeats.
- Previous studies indicated increased brain vessel density in HD.
- This study investigates alterations in vascular function and their mechanisms in HD.
Purpose of the Study:
- To determine if vascular function is altered in Huntington disease.
- To characterize the underlying mechanisms of vascular dysfunction in HD.
- To explore the role of astrocytes and pericytes in HD neurovascular changes.
Main Methods:
- Utilized 3D ΔR2-mMRA and BOLD/FAIR MRI to assess brain vessel density and vascular reactivity (VR) in HD mice.
- Quantified vascular endothelial growth factor (VEGF)-A and pericyte coverage using immunohistochemistry and ELISA.
- Examined astrocytes and pericytes from human and mouse brain samples, including iPSC-derived human astrocytes.
Main Results:
- Mutant huntingtin (mHTT) expression in astrocytes and neurons increased brain vessel density in HD mice.
- HD mice exhibited gradually impaired VR to carbogen, as shown by BOLD and FAIR MRI.
- HD astrocytes contained elevated VEGF-A, promoting endothelial cell proliferation and neurovascular changes.
- Astrocytic inflammation in HD reduced pericyte survival via an IκB kinase-dependent pathway, leading to decreased pericyte coverage.
Conclusions:
- Inflammation-prone HD astrocytes contribute to reduced pericyte coverage by promoting angiogenesis and pericyte loss.
- These vascular changes, including impaired VR, may explain hindered cerebral hemodynamics in HD.
- The findings suggest that impaired vascular function exacerbates brain atrophy during HD progression.
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.
