Xiao-Di Hao1, Chen-Sheng Le1, Hong-Mei Zhang1, De-Sheng Shang2, Lu-Sha Tong1, Feng Gao1. 1. School of Medicine, Department of Neurology, The Second Affiliated Hospital, Zhejiang University, Hangzhou, China. 2. School of Medicine, Department of Radiology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
Abstract
AIMS: Previous studies indicated that intraventricular injection of thrombin would induce hydrocephalus. But how thrombin works in this process remains unclear. Since cadherin plays a critical role in hydrocephalus, we aimed to explore the mechanisms of how thrombin acted on choroid plexus vascular endothelium and how thrombin interacted with vascular endothelial-cadherin (VE-cadherin) during hydrocephalus. METHODS: There were two parts in this study. Firstly, rats received an injection of saline or thrombin into the right lateral ventricle. Magnetic resonance imaging was applied to measure the lateral ventricle volumes. Albumin leakage and Evans blue content were assessed to test the blood-brain barrier function. Immunofluorescence and Western blot were applied to detect the location and the expression of VE-cadherin. Secondly, we observed the roles of protease-activated receptors-1 (PAR1) inhibitor (SCH79797), Src inhibitor (PP2), p21-activated kinase-1 (PAK1) inhibitor (IPA3) in the thrombin-induced hydrocephalus, and their effects on the regulation of VE-cadherin. RESULTS: Our study demonstrated that intraventricular injection of thrombin caused significant downregulation of VE-cadherin in choroid plexus and dilation of ventricles. In addition, the inhibition of PAR1/p-Src/p-PAK1 pathway reversed the decrease of VE-cadherin and attenuated thrombin-induced hydrocephalus. CONCLUSIONS: Our results suggested that the thrombin-induced hydrocephalus was associated with the inhibition of VE-cadherin via the PAR1/p-Src/p-PAK1 pathway.
AIMS: Previous studies indicated that intraventricular injection of thrombin would induce hydrocephalus. But how thrombin works in this process remains unclear. Since cadherin plays a critical role in hydrocephalus, we aimed to explore the mechanisms of how thrombin acted on choroid plexus vascular endothelium and how thrombin interacted with vascular endothelial-cadherin (VE-cadherin) during hydrocephalus. METHODS: There were two parts in this study. Firstly, rats received an injection of saline or thrombin into the right lateral ventricle. Magnetic resonance imaging was applied to measure the lateral ventricle volumes. Albumin leakage and Evans blue content were assessed to test the blood-brain barrier function. Immunofluorescence and Western blot were applied to detect the location and the expression of VE-cadherin. Secondly, we observed the roles of protease-activated receptors-1 (PAR1) inhibitor (SCH79797), Src inhibitor (PP2), p21-activated kinase-1 (PAK1) inhibitor (IPA3) in the thrombin-induced hydrocephalus, and their effects on the regulation of VE-cadherin. RESULTS: Our study demonstrated that intraventricular injection of thrombin caused significant downregulation of VE-cadherin in choroid plexus and dilation of ventricles. In addition, the inhibition of PAR1/p-Src/p-PAK1 pathway reversed the decrease of VE-cadherin and attenuated thrombin-induced hydrocephalus. CONCLUSIONS: Our results suggested that the thrombin-induced hydrocephalus was associated with the inhibition of VE-cadherin via the PAR1/p-Src/p-PAK1 pathway.
Authors: Jason K Karimy; Jinwei Zhang; David B Kurland; Brianna Carusillo Theriault; Daniel Duran; Jesse A Stokum; Charuta Gavankar Furey; Xu Zhou; M Shahid Mansuri; Julio Montejo; Alberto Vera; Michael L DiLuna; Eric Delpire; Seth L Alper; Murat Gunel; Volodymyr Gerzanich; Ruslan Medzhitov; J Marc Simard; Kristopher T Kahle Journal: Nat Med Date: 2017-07-10 Impact factor: 53.440
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