Deficiency of volume-regulated ClC-3 chloride channel attenuates cerebrovascular remodelling in DOCA-salt hypertension.
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.
['Zheng|Ling-Yun|LY|', 'Li|Lei|L|', 'Ma|Ming-Ming|MM|', 'Liu|Yun|Y|', 'Wang|Guan-Lei|GL|', 'Tang|Yong-Bo|YB|', 'Zhou|Jia-Guo|JG|', 'Lv|Xiao-Fei|XF|', 'Du|Yan-Hua|YH|', 'Guan|Yong-Yuan|YY|']
D000818:Animals D001488:Basilar Artery D001794:Blood Pressure D001835:Body Weight D018118:Chloride Channels D064791:Desoxycorticosterone Acetate D005353:Fibronectins D006973:Hypertension D020778:Matrix Metalloproteinase 2 D020780:Matrix Metalloproteinase 9 D051379:Mice D008810:Mice, Inbred C57BL D010766:Phosphorylation D051900:Smad3 Protein D053773:Transforming Growth Factor beta1
ClC-3 Cerebrovascular remodelling Hypertension MMP TGF-β1