Endothelial injury and inflammatory response induced by hemodynamic changes preceding intracranial aneurysm formation: experimental study in rats

Mohammad A. Jamous M.D., Ph.D., Shinji Nagahiro M.D., Ph.D., Keiko T. Kitazato B.S., Tetsuya Tamura M.D., Hani Abdel Aziz M.D., Masayuki Shono Ph.D., and Koichi Satoh M.D., Ph.D.
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Object

Intracranial aneurysms are the leading cause of subarachnoid hemorrhage, which is associated with high morbidity and mortality rates. Despite advances in the microsurgical and endovascular treatment of intracranial aneurysms, little is known about the mechanisms by which they originate, grow, and rupture. To clarify the series of early events leading to formation of intracranial aneurysms, the authors compared aneurysmal morphological changes on vascular corrosion casts with parallel pathological changes in the cerebral arteries of rats.

Methods

The authors induced cerebral aneurysms by renal hypertension and right common carotid artery ligation in 40 male Sprague–Dawley rats; 10 intact rats served as the controls. The anterior cerebral artery–olfactory artery bifurcation was assessed morphologically by using vascular corrosion casts of Batson plastic reagent and immunohis-tochemically by using antibodies against endothelial nitric oxide synthase, α–smooth muscle actin, macrophages, and matrix metalloproteinase–9.

Results

Surgically treated rats manifested different degrees of aneurysmal changes. Based on these staged changes, the authors propose that the formation of intracranial aneurysms starts with endothelial injury at the apical intimal pad (Stage I); this leads to the formation of an inflammatory zone (Stage II), followed by a partial tear or defect in the inflammatory zone. Expansion of this defect forms the nidus of the intracranial aneurysm (Stage III).

Conclusions

This is the first study to demonstrate the in vivo mechanisms of intracranial aneurysm formation. The inflammatory response that follows endothelial injury is the basic step in the pathogenesis of these lesions. In this study the investigators have expanded the understanding of the origin of intracranial aneurysms and have contributed to the further development of measures to prevent and treat aneurysms.

Abbreviations used in this paper:ACA–OlfA = anterior cerebral artery–olfactory artery; α-SMA = α–smooth muscle actin; CCA = common carotid artery; eNOS = endothelial nitric oxide synthase; MMP-9 = matrix metalloproteinase–9; PBS = phosphate-buffered saline; SAH = subarachnoid hemorrhage; SMC = smooth-muscle cell.

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Contributor Notes

Address reprint requests to: Mohammad A. Jamous, M.D., Ph.D., Department of Neurosurgery, School of Medicine, The University of Tokushima, 3-18-15 Kuramotocho, Tokushima City, Tokushima 770-8503, Japan. email: mojamous@yahoo.com.
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