Metformin Preserves VE–Cadherin in Choroid Plexus and Attenuates Hydrocephalus via VEGF/VEGFR2/p-Src in an Intraventricular Hemorrhage Rat Model

Abstract

Hydrocephalus induced by intraventricular hemorrhage (IVH) is associated with unfavorable prognosis. The increased permeability of choroid plexus and breakdown of the blood–brain barrier (BBB) was reported as a prominent mechanism of IVH-induced hydrocephalus, and vascular endothelial–cadherin (VE–cadherin) was demonstrated to be relevant. Metformin was reported to protect endothelial junction and preserve permeability widely; however, its role in hydrocephalus remains unclear. In this study, the decreased expression of VE–cadherin in the choroid plexus, accompanied with ventricle dilation, was investigated in an IVH rat model induced by intraventricular injection of autologous blood. Metformin treatment ameliorated hydrocephalus and upregulated VE–cadherin expression in choroid plexus meanwhile. We then observed that the internalization of VE–cadherin caused by the activation of vascular endothelial growth factor (VEGF) signaling after IVH was related to the occurrence of hydrocephalus, whereas it can be reversed by metformin treatment. Restraining VEGF signaling by antagonizing VEGFR2 or inhibiting Src phosphorylation increased the expression of VE–cadherin and decreased the severity of hydrocephalus after IVH. Our study demonstrated that the internalization of VE–cadherin via the activation of VEGF signaling may contribute to IVH-induced hydrocephalus, and metformin may be a potential protector via suppressing this pathway.

Correlation of P352L, R538G Col4A1 Gene, RS951733 Col4A2 Gene Locus Polymorphisms, IFN-, IL-17, and VE-Cadherin Levels with the Event of Non-Lobar Spontaneous Intracerebral Hemorrhage in Hypertension Patients: Research Protocol (Preprint)

“…In a mouse model of IVH, VE-cadherin levels are decreased in the choroid plexus, contributing to the development of hydrocephalus. Metformin has been identified as a potential protective agent because it maintains VE-cadherin expression in the choroid plexus, which is dependent on the suppression of the VEGF/ VEGFR2/p-Src pathway[20]. In addition, the interaction of VE-cadherin with other proteins such as p120-catenin and β-catenin is critical for maintaining vascular integrity.…”

“…In addition, the interaction of VE-cadherin with other proteins such as p120-catenin and β-catenin is critical for maintaining vascular integrity. Loss of VE-cadherin function can disrupt junctional complexes and alter the localization of other junctional proteins, leading to increased vascular permeability and impaired BBB function[20]. These findings suggest that VE-cadherin is a key player in the pathophysiology of ICH and associated complications, making it a promising target for developing therapies aimed at protecting the BBB and improving patient outcomes after intracranial hemorrhage incidents.…”