Reduction of endothelial tight junction proteins is related to cerebral aneurysm formation in rats
Reduction of endothelial tight junction proteins is related to cerebral aneurysm formation in rats
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DOI：
10.1097/hjh;0b013e32833c2273
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发表时间：
2010-09-01
影响因子：
4.9
通讯作者：
Nagahiro, Shinji
中科院分区：
文献类型：
--
作者：
Tada, Yoshiteru;Yagi, Kenji;Nagahiro, Shinji
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.Conclusion In rats, the destruction of tight junctions may facilitate macrophage migration and cerebral-aneurysm formation. J Hypertens 28:1883-1891 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
