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Excessive shear stress sensing on the arterial endothelium initiates cerebral aneurysm formation
Author(s) -
Fukuda Miyuki,
Fukuda Shunichi,
Ando Joji,
Yamamoto Kimiko,
Ito Yuki,
Inoue Takayuki,
Tsukahara Tetsuya,
Asahara Noriko,
Hasegawa Koji,
Shimazu Akira
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.712.11
Subject(s) - aneurysm , subarachnoid hemorrhage , medicine , endothelium , pathogenesis , ligation , paroxetine , cardiology , surgery , hippocampus , antidepressant
Although rupture of cerebral aneurysms is a major cause of life‐threatening subarachnoid hemorrhage, there are no effective therapeutic drugs for the treatment of aneurysms, partly because the pathogenesis of the aneurysm remains unresolved. We hypothesize that shear stress‐related hemodynamics initiates cerebral aneurysm formation. To test this hypothesis, we examined here whether disruption or inhibition of the endothelial shear stress sensor, P2X4 purinoceptor, has any influence on expressions of known contributors to aneurysm formation or not. P2X4 purinoceptor deficient (P2X4 KO) mice and Sprague‐Dawley rats were subjected to cerebral aneurysm‐generating surgery with ligation of unilateral common carotid artery and renal hypertension. P2X4 purinoceptor inhibitor, paroxetine (8 mg/kg/day) was administered to rats after the surgery. The incidence of aneurysm formation was examined with light microscopy, and expressions of contributors to aneurysm formation using a quantitative real‐time PCR analysis and immunohistochemical examinations. The frequency of aneurysm induction in P2X4 KO mice was significantly lower than wild‐type mice ( p =0.018). In addition, paroxetine significantly attenuated the incidence of induced aneurysms in rats after aneurysm‐generating surgery (p=0.031). Expression levels of inflammatory contributors to aneurysm formation, COX‐2, TNFα, MCP‐1, IL1β, and iNOS, were significantly increased in rats after aneurysm‐inducing surgery than control non‐operated animals by a quantitative real‐time PCR analysis. Paroxetine significantly reduced the expression levels of all the contributors. These data suggest that shear sensing on the arterial endothelium initiates chronic inflammation in the arterial wall during cerebral aneurysm formation. Because paroxetine has been used for human as an antidepressant, clinical use of this P2X4 purinoceptor inhibitor is expected as a novel therapy for cerebral aneurysms. Support or Funding Information This work is supported by Japan Agency for Medical Research and development, AMED and JSPS KAKENHI Grant Number JP15K10323. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .