Zheng L.-Y.,Cardiac and Cerebral Vascular Research Center |
Zheng L.-Y.,Guangdong Pharmaceutical University |
Li L.,Cardiac and Cerebral Vascular Research Center |
Ma M.-M.,Cardiac and Cerebral Vascular Research Center |
And 7 more authors.
Cardiovascular Research | Year: 2013
Aims: We have previously demonstrated that ClC-3 chloride channel activity and expression are significantly increased in re-modelled cerebral vessels of hypertensive rats. This study aims to examine whether this channel directly regulates cere-brovascular 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 byelectron microscopy revealed obvious disarray of SMCs and extracellular matrix accumulation. Immunofluorescence analysis showed that fibronectin was overex-pressed 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 basilarartery from remodelling. The vascular structure injury in ClC-3+/+ hypertensive micewas accompanied by significantly increased expression of matrix metalloproteinase (MMP)-2, membrane-type (MT)1-MMP, and tissue inhibitor of metalloproteinase (TIMP)-2, which was inhibitedbyClC-3 knockout. Additionally, the increaseintrans-forming growth factor (TGF)-b1 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-b1/Smad3 signalling pathway in this hypertension. © The Author 2013.