title: TRPC3 channel confers cerebrovascular remodelling during hypertension via transactivation of EGF receptor signalling.
abstract: OBJECTIVE
  Ionic perturbation in vascular smooth muscle cells contributes to cerebrovascular remodelling in the setting of hypertension, but the role of transient receptor potential (TRP) channel superfamily remains unknown. The present study was conducted to define the contribution of TRP channels to cerebrovascular remodelling.
  
  
  RESULTS
  By integrating quantitative PCR, western blotting, patch clamping, and Ca(2+) imaging, we identified TRP channel, subfamily canonical, member 3 (TRPC3) as the channel subtype most considerably elevated in basilar arteries of two-kidney, two-clip stroke-prone hypertensive rats. Importantly, administration of pyrazole 3 (Pyr3), a TRPC3 channel blocker, attenuated cerebrovascular remodelling. During hypertension, epidermal growth factor receptor (EGFR) was transactivated, as evidenced by marked EGFR phosphorylation, increased pro-HB-EGF shedding, and elevated activity of ADAM17 (HB-EGF sheddase). ADAM17 activity was increased owing to enhanced activation rather than elevated expression. Remarkably, Pyr3 treatment suppressed EGFR transactivation in hypertension. In proliferating basilar artery smooth muscle cells or basilar arteries of hypertensive rats, co-immunoprecipitation assay revealed an interaction between TRPC3 and ADAM17 upon Ang II stimulation.
  
  
  CONCLUSIONS
  Collectively, we demonstrated that enhanced EGFR transactivation, due to increased TRPC3 expression and functional coupling of TRPC3/ADAM17, resulted in cerebrovascular remodelling. Therefore, TRPC3-induced EGFR transactivation may be therapeutically exploited to prevent hypertension-induced cerebrovascular remodelling.
authors.affiliation: Department of Cardiology, The Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha, Hunan 410011, China mwang823@gmail.com zzhang@csu.edu.cn.
authors.forename: Mi
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Yong-Bo
authors.initials: YB
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, China.
authors.forename: Jing-Hui
authors.initials: JH
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, No. 110 Xiangya Road, Hunan 410078, China Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China.
authors.forename: Chang-Ping
authors.initials: CP
authors.lastname: Hu
authors.affiliation: Department of Cardiology, The Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha, Hunan 410011, China.
authors.forename: Shui-Ping
authors.initials: SP
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, The Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha, Hunan 410011, China.
authors.forename: Dao-Quan
authors.initials: DQ
authors.lastname: Peng
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Jia-Guo
authors.initials: JG
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Yong-Yuan
authors.initials: YY
authors.lastname: Guan
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, No. 110 Xiangya Road, Hunan 410078, China Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China mwang823@gmail.com zzhang@csu.edu.cn.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D051722:ADAM Proteins / Q000502:physiology; D000072198:ADAM17 Protein; D000818:Animals; D001921:Brain / Q000098:blood supply*; D020013:Calcium Signaling; D066246:ErbB Receptors / Q000502:physiology*; D006973:Hypertension / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D015533:Transcriptional Activation; D066253:Vascular Remodeling
chemical_list: D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C512478:EGFR protein, human; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat
keywords: Angiotensin II; Cerebrovascular remodelling; Hypertension; TRPC3