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Juhana Frösen, Juan Cebral, Anne M. Robertson and Tomohiro Aoki

OBJECTIVE

Unruptured intracranial aneurysms (UIAs) are relatively common lesions that may cause devastating intracranial hemorrhage, thus producing considerable suffering and anxiety in those affected by the disease or an increased likelihood of developing it. Advances in the knowledge of the pathobiology behind intracranial aneurysm (IA) formation, progression, and rupture have led to preclinical testing of drug therapies that would prevent IA formation or progression. In parallel, novel biologically based diagnostic tools to estimate rupture risk are approaching clinical use. Arterial wall remodeling, triggered by flow and intramural stresses and mediated by inflammation, is relevant to both.

METHODS

This review discusses the basis of flow-driven vessel remodeling and translates that knowledge to the observations made on the mechanisms of IA initiation and progression on studies using animal models of induced IA formation, study of human IA tissue samples, and study of patient-derived computational fluid dynamics models.

RESULTS

Blood flow conditions leading to high wall shear stress (WSS) activate proinflammatory signaling in endothelial cells that recruits macrophages to the site exposed to high WSS, especially through macrophage chemoattractant protein 1 (MCP1). This macrophage infiltration leads to protease expression, which disrupts the internal elastic lamina and collagen matrix, leading to focal outward bulging of the wall and IA initiation. For the IA to grow, collagen remodeling and smooth muscle cell (SMC) proliferation are essential, because the fact that collagen does not distend much prevents the passive dilation of a focal weakness to a sizable IA. Chronic macrophage infiltration of the IA wall promotes this SMC-mediated growth and is a potential target for drug therapy. Once the IA wall grows, it is subjected to changes in wall tension and flow conditions as a result of the change in geometry and has to remodel accordingly to avoid rupture. Flow affects this remodeling process.

CONCLUSIONS

Flow triggers an inflammatory reaction that predisposes the arterial wall to IA initiation and growth and affects the associated remodeling of the UIA wall. This chronic inflammation is a putative target for drug therapy that would stabilize UIAs or prevent UIA formation. Moreover, once this coupling between IA wall remodeling and flow is understood, data from patient-specific flow models can be gathered as part of the diagnostic workup and utilized to improve risk assessment for UIA initiation, progression, and eventual rupture.

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Tomohiro Aoki, Masaki Nishimura, Ryota Ishibashi, Hiroharu Kataoka, Yasushi Takagi and Nobuo Hashimoto

Object

The pathophysiological origin of cerebral aneurysms is closely associated with chronic inflammation in arterial walls. Recently, the authors identified nuclear factor–kappa B (NF-κB) as a key mediator of cerebral aneurysm formation and progression. Because Toll-like receptor 4 (TLR4) stimulates NF-κB activation in arterial walls in atherosclerosis, the authors hypothesize that TLR4 expresses in cerebral aneurysms and contributes to the activation of NF-κB in cerebral aneurysm walls.

Methods

Cerebral aneurysms were induced in male Sprague-Dawley rats. Expression of TLRs in cerebral aneurysm walls was assessed using reverse transcriptase polymerase chain reaction (RT-PCR). The expression of TLR4 was examined using RT-PCR, immunohistochemical studies, and Western blotting. To assess TLR4 dependency on NF-κB activation, double immunostaining and a study using NF-κB–deficient mice were done. Finally, TLR4 expression in human cerebral aneurysm walls was assessed using immunohistochemical studies.

Results

In cerebral aneurysm walls, TLR1, -4, -5, -6, -10, and -11 were expressed. Among them, TLR4 and TLR10 expression changed during cerebral aneurysm formation. Expression of TLR4 was predominantly in the endothelial cell layer of cerebral aneurysm walls, and was transitionally upregulated at the early stage of cerebral aneurysm formation. The TLR4 expression coincided well with NF-κB activation. In human cerebral aneurysms, TLR4 was also expressed in the endothelial cell layer, as it was in rats.

Conclusions

Toll-like receptor 4 was expressed in cerebral aneurysm walls both in rats and humans. This receptor may play a crucial role in cerebral aneurysm formation through NF-κB activation in endothelial cells. The results of the present study will shed new light on the pathogenesis of cerebral aneurysm formation.

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Haruka Miyata, Hirohiko Imai, Hirokazu Koseki, Kampei Shimizu, Yu Abekura, Mieko Oka, Takakazu Kawamata, Tetsuya Matsuda, Kazuhiko Nozaki, Shuh Narumiya and Tomohiro Aoki

OBJECTIVE

Subarachnoid hemorrhage (SAH) has a poor outcome despite modern advancements in medical care. The development of a novel therapeutic strategy to prevent rupture of intracranial aneurysms (IAs) or a novel diagnostic marker to predict rupture-prone lesions is thus mandatory. Therefore, in the present study, the authors established a rat model in which IAs spontaneously rupture and examined this model to clarify histopathological features associated with rupture of lesions.

METHODS

Female Sprague Dawley rats were subjected to bilateral ovariectomy; the ligation of the left common carotid, the right external carotid, and the right pterygopalatine arteries; induced systemic hypertension; and the administration of a lysyl oxidase inhibitor.

RESULTS

Aneurysmal SAH occurred in one-third of manipulated animals and the locations of ruptured IAs were exclusively at a posterior or anterior communicating artery (PCoA/ACoA). Histopathological examination using ruptured IAs, rupture-prone IAs induced at a PCoA or ACoA, and IAs induced at an anterior cerebral artery–olfactory artery bifurcation that never ruptured revealed the formation of vasa vasorum as an event associated with rupture of IAs.

CONCLUSIONS

The authors propose the contribution of a structural change in an adventitia, i.e., vasa vasorum formation, to the rupture of IAs. Findings from this study provide important insights about the pathogenesis of IAs.