title: Reduction of endothelial tight junction proteins is related to cerebral aneurysm formation in rats.
abstract: OBJECTIVE
  The formation of cerebral aneurysms is associated with endothelial damage and macrophage migration. Hypothesizing that the opening of tight junctions due to the disappearance of the tight junction proteins occludin and zona occludens-1 (ZO-1) in damaged endothelia allows macrophage migration, leading to cerebral aneurysm formation, we investigated the role of tight junction proteins.
  
  
  METHODS
  The vascular wall of female rats subjected to hypertension, oophorectomy (OVX), and hemodynamic stress to induce cerebral aneurysms was evaluated morphologically, immunohistochemically, and by quantitative RT-PCR. We also assessed the regulation of tight junction proteins in human brain endothelial cells (HBECs).
  
  
  RESULTS
  In the very early stage before aneurysm formation, the expression of occludin and ZO-1 was reduced in injured endothelial cell junctions exhibiting gaps. In the course of aneurysmal progression their reduction progressed and was correlated with macrophage migration. In hypertension along with OVX rats we observed an increase in angiotensin II and the degradation molecules matrix metalloproteinase-9 (MMP-9), nicotinamide-adenine dinucleotide phosphate oxidases and monocyte chemoattractant protein-1. The mineralocorticoid receptor blocker eplerenone increased occludin and ZO-1 expression; this was associated with a reduction in angiotensin II and the degradation molecules and resulted in the inhibition of macrophage exudation and aneurysm formation. In HBECs, occludin and ZO-1 downregulation by angiotensin II and estrogen deficiency was reversed by eplerenone, the MMP inhibitor SB3CT, and apocynin. Our results suggest that macrophage migration is associated with the reduction in tight junction proteins induced by the degradation molecules.
  
  
  CONCLUSIONS
  In rats, the destruction of tight junctions may facilitate macrophage migration and cerebral-aneurysm formation.
authors.affiliation: Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. yoshiteru.tada@hotmail.co.jp
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Tada
authors.forename: Kenji
authors.initials: K
authors.lastname: Yagi
authors.forename: Keiko T
authors.initials: KT
authors.lastname: Kitazato
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tamura
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kinouchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimada
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Matsushita
authors.forename: Norio
authors.initials: N
authors.lastname: Nakajima
authors.forename: Junichiro
authors.initials: J
authors.lastname: Satomi
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Kageji
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
mesh_terms: D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077545:Eplerenone; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D062793:Occludin; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D062826:Zonula Occludens-1 Protein
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D017931:DNA Primers; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568987:Ocln protein, rat; D010750:Phosphoproteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C569042:TJP1 protein, human; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D013148:Spironolactone; D000077545:Eplerenone; D020780:Matrix Metalloproteinase 9