Reductionof endothelial tight junction proteins on experimental cerebral aneurysm in rats

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591686
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: The University of Tokushima
• Principal Investigator: NISHI Kyoko The University of Tokushima, 大学院・ヘルスバイオサイエンス研究部, 講師 (60335817)
• Co-Investigator(Kenkyū-buntansha): NAGAHIRO Shinji 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 教授 (60145315) ; KANEMATSU Yasuhisa 徳島大学, 病院, 助教 (90363142) ; UNO Masaaki 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授 (90232884) ; MATSUBARA Shunji 徳島大学, 病院, 講師 (60294675) ; YAGI KENJI 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 助教 (80551837) ; TADA Yoshiteru 徳島大学, 病院, 助教 (30547964)
• Project Period (FY): 2008 – 2010
• Keywords: 脳動脈瘤 / タイトジャンクション蛋白 / mineral corticoid receptor / phosphodiesterase / 血管内皮障害 / angiotensin II / エストロゲン / 炎症 / ラット

Research Abstract

The formation of cerebral aneurysms is associated with endothelial damage and macrophage migration. Hypothesizing that the opening of tight junctions (TJs) due to the disappearance of the TJ proteins occludin and zona occludens-1 (ZO-1) in damaged endothelia facilitates macrophage migration, leading to cerebral aneurysm formation, we investigated the role of TJ proteins. To induce cerebral aneurysms, we used female rats subjected to hypertension (HT), oophorectomy (OVX), and hemodynamic stress and evaluated the vascular wall morphologically, immunohistochemically, and by quantitative RT-PCR. We also assessed the regulation of TJ proteins in human brain endothelial cells (HBECs). In the very early stage before aneurysm formation, the expression of occludin and ZO-1was reduced in injured endothelial cell junctions exhibiting gaps. In the course of aneurysmal progression their reduction progressed and was correlated with macrophage migration. In HT+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-1expression; 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-1down-regulation 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 TJ proteins induced by the degradation molecules.

Research Products

• [Journal Article] Statins Promote the Growth of Experimentally-induced Cerebral Aneurysms in Estrogen-Deficient Rats (2011)
  • Author(s): Tada Y, Kitazato KT, Yagi K, Shimada K, Matsushita N, Kinouchi T, Kanematsu Y, Satomi J, Kageji T, Nagahiro S
  • Journal Title: Stroke in press
• [Journal Article] Reduction of endothelial tight junction proteins is related to cerebral aneurysm formation in rats. (2010)
  • Author(s): Tada Y, Yagi K, Kitazato KT, Tamura T, Kinouchi T, Shimada K, Matsushita N, Nakajima N, Satomi J, Kageji T, Nagahiro S.
  • Journal Title: J Hypertens. 28 Pages: 1883-1891
• [Journal Article] Ibudilast inhibits cerebral aneurysms by down-regulating inflammation-related molecules in the vascular wall of rats. (2010)
  • Author(s): Yagi K, Tada Y, Kitazato KT, Tamura T, Satomi J, Nagahiro S.
  • Journal Title: Neurosurgery. 66 Pages: 551-559
• [Journal Article] Role of mineralocorticoid receptor on experimental cerebral aneurysms in rats. (2009)
  • Author(s): Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, Satomi J, Nagahiro S.
  • Journal Title: Hypertension. 54 Pages: 552-557
• [Journal Article] Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats. (2009)
  • Author(s): Tamura T, Jamous MA, Kitazato KT, Yagi K, Tada Y, Uno M, Nagahiro S.
  • Journal Title: J Hypertens. 27 Pages: 1284-12892
• [Presentation] Cyclic Nucleotide Phosphodiesterase 4-Related Vascular Inflammation Contributes to the Progression of Cerebral Aneurysms (2009)
  • Author(s): Yagi K, Kitazato KT, Tada Y, Tamura T, Matsuzaki K, Satomi J, Nagahiro S.
  • Organizer: XIV world Congress of Neurological Surgery
  • Place of Presentation: Boston, USA
  • Year and Date: 20090830-20090904
• [Presentation] Eplerenone suppresses the progression of experimentally-induced cerebral aneurysms in rats (2009)
  • Author(s): Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, Matsushita N, Satomi J, Nagahiro S.
  • Organizer: XIV world Congress of Neurological Surgery
  • Place of Presentation: Boston, USA
  • Year and Date: 20090830-20090904
• [Presentation] Role of mineral corticoid receptor on experimental cerebral aneurysms in rats 2009 (2009)
  • Author(s): Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, Satomi J, Nagahiro S.
  • Organizer: The 6th International Intracranial Stent meeting
  • Place of Presentation: Sendai, Japan
  • Year and Date: 20090805-20090807
• [Presentation] What should we do to prevent cerebral aneurysm formation and progression (2008)
  • Author(s): Nagahiro S, Tamura T, Yagi K, Tada Y, Jamous MA, Uno M, Nakajima N, Matsubara S, Kitazato KT
  • Organizer: 6th World Stroke Congress
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20080924-20080927
• [Presentation] Leucocyte adhesion molecules contribute to the development of cerebral aneurysms in rats (2008)
  • Author(s): Yagi K, Kitazato KT, Tada Y, Tamura T, Nakajima N, Matsubara S, Nagahiro S.
  • Organizer: 6th World Stroke Congress
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20080924-20080927
• [Presentation] Role of mineral corticoid receptor on experimental cerebral aneurysms in rats (2008)
  • Author(s): Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, Satomi J, Nagahiro S.
  • Organizer: 6th World Stroke Congress
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20080924-20080927
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