title: Deficiency of volume-regulated ClC-3 chloride channel attenuates cerebrovascular remodelling in DOCA-salt hypertension.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan 2 Rd, Guangzhou 510080, PR China.
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Zheng
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Ma
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Guan-Lei
authors.initials: GL
authors.lastname: Wang
authors.forename: Yong-Bo
authors.initials: YB
authors.lastname: Tang
authors.forename: Jia-Guo
authors.initials: JG
authors.lastname: Zhou
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Lv
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Du
authors.forename: Yong-Yuan
authors.initials: YY
authors.lastname: Guan
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000473:pathology*; D001794:Blood Pressure; D001835:Body Weight; D018118:Chloride Channels / Q000172:deficiency / Q000502:physiology*; D064791:Desoxycorticosterone Acetate; D005353:Fibronectins / Q000032:analysis; D006973:Hypertension / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051900:Smad3 Protein / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000097:blood / Q000502:physiology
chemical_list: D018118:Chloride Channels; C115376:ClC-3 channel; D005353:Fibronectins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D064791:Desoxycorticosterone Acetate; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Cerebrovascular remodelling; ClC-3; Hypertension; MMP; TGF-β1