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- Title
Deficiency of volume-regulated ClC-3 chloride channel attenuates cerebrovascular remodelling in DOCA-salt hypertension.
- Authors
Zheng, Ling-Yun; Li, Lei; Ma, Ming-Ming; Liu, Yun; Wang, Guan-Lei; Tang, Yong-Bo; Zhou, Jia-Guo; Lv, Xiao-Fei; Du, Yan-Hua; Guan, Yong-Yuan
- Abstract
Aims We have previously demonstrated that ClC-3 chloride channel activity and expression are significantly increased in remodelled cerebral vessels of hypertensive rats. This study aims to examine whether this channel directly regulates cerebrovascular remodelling during hypertension by using ClC-3−/− mice. Methods and results After DOCA-salt treatment, medial cross-sectional area, media thickness, and media–lumen ratio of the basilar artery of ClC-3+/+ mice were significantly increased, accompanied by reduced lumen diameter, indicating apparent vascular remodelling. The vascular ultrastructure of ClC-3+/+ hypertensive mice by electron microscopy revealed obvious disarray of SMCs and extracellular matrix accumulation. Immunofluorescence analysis showed that fibronectin was overexpressed in ClC-3+/+ DOCA-salt mice. All of these vascular structure alterations were prevented in ClC-3−/− mice despite DOCA-salt treatment. However, propranolol, which reduced blood pressure as effectively as ClC-3 deficiency, failed to prevent basilar artery from remodelling. The vascular structure injury in ClC-3+/+ hypertensive mice was accompanied by significantly increased expression of matrix metalloproteinase (MMP)-2, membrane-type (MT)1-MMP, and tissue inhibitor of metalloproteinase (TIMP)-2, which was inhibited by ClC-3 knockout. Additionally, the increase in transforming growth factor (TGF)-β1 level in serum, as well as phosphorylation of Smad3 at serine 423/425 in basilar artery, induced by DOCA-salt, was markedly prevented in ClC-3−/− mice. Conclusion Our findings suggest that ClC-3 deficiency attenuates cerebrovascular remodelling possibly via the suppression of MMPs/TIMP expression and TGF-β1/Smad3 signalling pathway in this hypertension.
- Subjects
CHLORIDE channels; HYPERTENSION; BRAIN disease treatment; CEREBROVASCULAR disease; GENE expression; ELECTRON microscopy; IMMUNOFLUORESCENCE; LABORATORY rats
- Publication
Cardiovascular Research, 2013, Vol 100, Issue 1, p134
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvt156