Thrombin disrupts vascular endothelial‐cadherin and leads to hydrocephalus via protease‐activated receptors‐1 pathway

Abstract

Summary 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.

Inhibition of PAR1 attenuates meningeal macrophage activation and vascular inflammation in a rat model of thrombin-induced hydrocephalus

“…It is well known that 50μl of whole blood produces 13 to 18 units of thrombin [22] and intraventricular infusion of 5 units of thrombin caused high mortality in our preliminary experiments. Thus, the amount of thrombin in this current study was 3 unites in 50μl saline, the same as our previous study [2,3].…”

“…Hydrocephalus is an independent risk factor of hemorrhage-associated morbidity [1]. Our previous study found that thrombin played a critical role in hydrocephalus [2,3]. Cerebrospinal fluid (CSF) is mainly produced in choroid plexus and absorbed in subarachnoid space, and the key point of hydrocephalus should be the changes in formation or absorption of CSF [4][5][6].…”

“…Cerebrospinal fluid (CSF) is mainly produced in choroid plexus and absorbed in subarachnoid space, and the key point of hydrocephalus should be the changes in formation or absorption of CSF [4][5][6]. Thrombin is produced immediately after hemorrhage stroke and plays an essential role in brain damage after intracerebral hemorrhage (ICH) [2, 3,7,8]. Thrombin could disrupt blood-cerebrospinal fluid (CSF) barrier and generate communicating hydrocephalus via proteinase-activated receptor 1 (PAR1) pathway, which leads to vascular endothelial-cadherin (VE-cadherin) downregulation in choroid plexus [2, 3,9].…”

“…Thrombin is produced immediately after hemorrhage stroke and plays an essential role in brain damage after intracerebral hemorrhage (ICH) [2, 3,7,8]. Thrombin could disrupt blood-cerebrospinal fluid (CSF) barrier and generate communicating hydrocephalus via proteinase-activated receptor 1 (PAR1) pathway, which leads to vascular endothelial-cadherin (VE-cadherin) downregulation in choroid plexus [2, 3,9]. Inflammation in the ventricular system is strongly associated with the blood-CSF barrier and hydrocephalus formation [9][10][11][12][13][14].…”

Hemorrhagic stroke—Pathomechanisms of injury and therapeutic options

“…In this special issue, Wan et al demonstrated that activation of epiplexus cells is associated with SAH‐ and thrombin‐induced hydrocephalus . The effect of thrombin in hydrocephalus development may be through protease‐activated receptor‐1 …”