Cerebral aneurysm formation in nitric oxide synthase-3 knockout mice.
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.
Abruzzo
Todd
T
The Neuroscience Institute: Section of Interventional and Endovascular Surgical Neuroradiology, Department of Neurosurgery, University of Cincinnati Colleges of Medicine and Engineering, Cincinnati, Ohio, USA. abruzzta@healthall.com
Kendler
Ady
A
Apkarian
Robert
R
Workman
Michael
M
Khoury
Jane C
JC
Cloft
Harry J
HJ
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D002532:Intracranial Aneurysm / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency*; D052250:Nitric Oxide Synthase Type III; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency
D017395:Plasminogen Activator Inhibitor 1; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse