title: Integrin β3 mediates cerebrovascular remodelling through Src/ClC-3 volume-regulated Cl(-) channel signalling pathway.
abstract: OBJECTIVE
  Cerebrovascular remodelling is one of the important risk factors of stroke. The underlying mechanisms are unclear. Integrin β3 and volume-regulated ClC-3 Cl(-) channels have recently been implicated as important contributors to vascular cell proliferation. Therefore, we investigated the role of integrin β3 in cerebrovascular remodelling and related Cl(-) signalling pathway.
  
  
  METHODS
  Cl(-) currents were recorded using a patch clamp technique. The expression of integrin β3 in hypertensive animals was examined by Western blot and immunohistochemisty. Immunoprecipitation, cDNA and siRNA transfection were employed to investigate the integrin β3/Src/ClC-3 signalling.
  
  
  RESULTS
  Integrin β3 expression was up-regulated in stroke-prone spontaneously hypertensive rats, 2-kidney 2-clip hypertensive rats and angiotensin II-infused hypertensive mice. Integrin β3 expression was positively correlated with medial cross-sectional area and ClC-3 expression in the basilar artery of 2-kidney 2-clip hypertensive rats. Knockdown of integrin β3 inhibited the proliferation of rat basilar vascular smooth muscle cells induced by angiotensin II. Co-immunoprecipitation and immunofluorescence experiments revealed a physical interaction between integrin β3, Src and ClC-3 protein. The integrin β3/Src/ClC-3 signalling pathway was shown to be involved in the activation of volume-regulated chloride channels induced by both hypo-osmotic stress and angiotensin II. Tyrosine 284 within a concensus Src phosphorylation site was the key point for ClC-3 channel activation. ClC-3 knockout significantly attenuated angiotensin II-induced cerebrovascular remodelling.
  
  
  CONCLUSIONS
  Integrin β3 mediates cerebrovascular remodelling during hypertension via Src/ClC-3 signalling pathway.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, China; Cardiac & Cerebral Vascular Research Center, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Zeng
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Wang
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Ma
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Lv
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Jia-Guo
authors.initials: JG
authors.lastname: Zhou
authors.forename: Yong-Yuan
authors.initials: YY
authors.lastname: Guan
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006973:Hypertension / Q000503:physiopathology*; D047468:Immunoprecipitation; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000209:etiology; D015854:Up-Regulation / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D018118:Chloride Channels; C115376:ClC-3 channel; D039661:Integrin beta3; D019061:src-Family Kinases
keywords: ClC-3; Src; cerebrovascular remodelling; chloride channel; integrin β3