Heritability of Intracerebral Hemorrhagic Lesions and Cerebral Aneurysms in the Rat

Coutard, Michèle; Wei, Huang; Osborne-Pellegrin, Mary

doi:10.1161/01.str.31.11.2678

Cited by 9 publications

(3 citation statements)

References 50 publications

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“…In non-human primates, rats, and wild type mice, consistent induction of saccular cerebral aneurysms has been possible using a combination of unilateral carotid artery ligation and artificially-induced systemic arterial hypertension (Coutard et al, 2000;Coutard et al, 1999;Coutard et al, 1997;Morimoto et al, 2002;Kim et al, 1989;Hashimoto et al, 1987;Hashimoto et al, 1979;Hashimoto, et al, 1978;Hazama et al, 1987). Unilateral carotid artery ligation alone has induced cerebral aneurysms in rats, albeit at a much lower frequency than carotid artery ligation combined with artificial hypertension (Coutard et al, 1997;Hashimoto et al, 1980).…”

Section: Introductionmentioning

confidence: 99%

Cerebral Aneurysm Formation in Nitric Oxide Synthase-3 Knockout Mice

Abruzzo¹,

Kendler²,

Apkarian³

et al. 2007

CNR

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We sought to evaluate the influence of specific vasoactive gene knockouts on the process of intracranial aneurysm formation in mice. Thirty wild type, 7 nitric oxide synthase (NOS)-2 knockout, 6 NOS-3 knockout, and 8 plasminogen activator inhibitor (PAI)-1 knockout female mice underwent left common carotid artery ligation at 2 to 6 months of age. After a survival period (average 20.4 months +/- 1.5 months), the brains were perfusion fixed with 10% buffered formalin for 10 minutes and then perfused with India ink. Brain and intact cerebral circulation were surgically removed and further fixed in 10% buffered formalin for 4 additional days. The basal cerebral circulation of each brain was examined for the presence of intracranial aneurysms under a surgical microscope (3x-21x). Suspected aneurysms were further dissected for histological analysis. Specimens were embedded in epoxy resin, cut into 0.5 and 1.0 micron sections, and stained with Toluidine blue. A neuropathologist blinded to genotype and surgical microscopy results examined the slides for evidence of aneurysmal pathology. Two intracranial aneurysms in 2 NOS-3 knockout mice were confirmed by histology. No intracranial aneurysms were confirmed in any wild type, NOS-2 knockout, or PAI-1 knockout mice. Histological analysis of aneurysms revealed loss of elastica, subendothelial collagen deposition, and perivascular lymphocytic infiltration. Our results suggest that NOS-3 knockout, but not PAI-1 or NOS-2 knockout, predisposes to the formation of intracranial aneurysms in mice subjected to unilateral carotid artery ligation. Due to small sample sizes however, selection bias cannot be excluded and further investigation is necessary to confirm our results.

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Section: Introductionmentioning

confidence: 99%

Cerebral Aneurysm Formation in Nitric Oxide Synthase-3 Knockout Mice

Abruzzo¹,

Kendler²,

Apkarian³

et al. 2007

CNR

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“…Using the above-described model of experimental CAs induced by unilateral carotid ligation associated with hypertension, we have previously shown that CA occurrence was different in various rat strains, suggesting a genetically determined susceptibility [9, 13]. In addition, enhanced flow created in some cerebral arteries merely by the ligation of one common carotid artery induced more aneurysmal structures in the Long Evans (LE) than in the Brown Norway (BN) [9].…”

Section: Introductionmentioning

confidence: 99%

High-Flow-Induced Arterial Remodeling in Rats with Different Susceptibilities to Cerebral Aneurysms

Coutard

Osborne-Pellegrin²,

Fontaine³

et al. 2006

J Vasc Res

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Background: The higher incidence of cerebral aneurysms (CAs) induced by enhanced arterial blood flow in Long Evans (LE) compared to Brown Norway (BN) rats suggests that intrinsic differences in high-flow arterial remodeling may be involved in determining CA susceptibility. Some aspects of this remodeling were compared in LE and BN rats after creation of an abdominal aortocaval fistula (ACF). Methods and Results: At 4 days with ACF, aortic luminal cross-sectional area (LCSA) determined by morphometry was increased by 20% in LE but not in BN rats. mRNA levels, determined by RT-PCR, were higher in LE than in BN rats for collagen α1(I), collagen α1(III), MMP2 and its inhibitor TIMP1 at 19 days with ACF. Nitric oxide synthase (NOS) mRNA levels were higher in LE rats at 4 days for the inducible (NOS2) isoform and at 4 and 19 days for the neuronal (NOS1) isoform. Aortic LCSA and NOS1 mRNA levels were tightly correlated and NOS inhibition prevented ACF-induced aortic remodeling in the LE rat. MMP2 and MMP7 activity, evaluated by zymography at 4 days with ACF, did not greatly differ between BN and LE. Conclusions: These data suggest that a higher intrinsic ability for high-flow-induced arterial enlargement associated with NOS gene overexpression may be a possible genetic determinant in CA susceptibility.

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“…During the past decade, information about haemodynamic regulation in cerebral blood vessels has given impetus to studies leading to the identification of gene variants that may be pathogenic. [36][37][38][39][40] Genetic predisposition to IA has long been suspected; 41,42 multiple genetic and environmental factors contribute to the risk. 42,43 The contribution of RAS gene polymorphisms to IA pathogenesis must therefore be viewed in a wider context.…”

Section: Multiple Genes Are Implicated In Predisposition To Intracranial Aneurysmmentioning

confidence: 99%

The role of the renin—angiotensin system in the pathogenesis of intracranial aneurysms

Shoja

Agutter²,

Tubbs

et al. 2011

J Renin Angiotensin Aldosterone Syst

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Introduction: Recent work has begun to elucidate the pathogenesis of intracranial aneurysms (IA) and has shown that many genes are involved in the risk for this condition. There has also been increasing research interest in the renin-angiotensin system (RAS) in the brain and its involvement in a range of cardiovascular and neurological disorders. The possibility that the RAS is implicated in the pathogenesis of IA merits further investigation. The aim of this article is to review the literature on the pathogenesis of IA and the pathophysiological significance of the brain RAS, and to identify directions for research into their association. Methods and results:A survey of the literature in these fields shows that although factors contributing to systemic hypertension predispose to IA, a large number of genes involved in endothelial cell adhesion, smooth muscle activity, extracellular matrix dynamics and the inflammatory and immune responses are also implicated. The brain RAS has a significant role in regulating blood pressure and in maintaining cerebrovascular autoregulation, but angiotensin II receptors are also involved in the maintenance of endothelial cell and vascular smooth muscle function and in the inflammatory response in the brain. Conclusions: There is strong, albeit largely circumstantial, evidence in the literature for a relationship between the brain RAS and the formation of IA. Research on the association between polymorphisms in RAS-related genes and the incidence of unruptured and ruptured IA is indicated.

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Heritability of Intracerebral Hemorrhagic Lesions and Cerebral Aneurysms in the Rat

Cited by 9 publications

References 50 publications

Cerebral Aneurysm Formation in Nitric Oxide Synthase-3 Knockout Mice

Cerebral Aneurysm Formation in Nitric Oxide Synthase-3 Knockout Mice

High-Flow-Induced Arterial Remodeling in Rats with Different Susceptibilities to Cerebral Aneurysms

The role of the renin—angiotensin system in the pathogenesis of intracranial aneurysms

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