The influence of hemodynamic forces on biomarkers in the walls of elastase-induced aneurysms in rabbits
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Biological and biophysical factors have been shown to play an important role in the initiation, progression, and rupture of intracranial aneurysms. The purpose of this study was to evaluate the association between hemodynamic forces and markers of vascular remodeling in elastase-induced saccular aneurysms in rabbits.
Elastase-induced aneurysms were created at the origin of the right common carotid artery in rabbits. Hemodynamic parameters were estimated using computational fluid dynamic simulations based on 3-D-reconstructed models of the vasculature. Expression of matrix metalloproteinases (MMPs), their inhibitors (TIMPs) and markers of vascular remodeling were measured in different spatial regions within the aneurysms.
Altered expression of biological markers relative to controls was correlated with the locations of subnormal time-averaged wall shear stress (WSS) but not with the magnitude of pressure. In the aneurysms, WSS was low and expression of biological markers was significantly altered in a time-dependent fashion. At 2 weeks, an upregulation of active-MMP-2, downregulation of TIMP-1 and TIMP-2, and intact endothelium were found in aneurysm cavities. However, by 12 weeks, endothelial cells were absent or scattered, and levels of pro- and active-MMP-2 were not different from those in control arteries, but pro-MMP-9 and both TIMPs were upregulated.
These results reveal a strong, spatially localized correlation between diminished WSS and differential expression of biological markers of vascular remodeling in elastase-induced saccular aneurysms. The ability of the wall to function and maintain a healthy endothelium in a low shear environment appears to be significantly impaired by chronic exposure to low WSS.
KeywordsHemodynamics Shear stress Aneurysm Matrix metalloproteinases
This work was supported by a research grant from the National Institutes of Health (NS42646-01). The authors thank Dr. Virginia Miller and Dr. Muthuvel Jayachandran, Department of Physiology and Surgery, and Dr. Zvonimir Katusic for their generous help on the project.
- 6.Juvela S, Porras M, Poussa K (2000) Natural history of unruptured intracranial aneurysms: probability and risk factors for aneurysm rupture. Neurosurg Focus 8:Preview 1Google Scholar
- 11.Sogawa K, Kondo K, Fujino H, Takahashi Y, Miyoshi T, Sakiyama S, Mukai K, Monden Y (2003) Increased expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 is correlated with poor prognostic variables in patients with thymic epithelial tumors. Cancer 98:1822–1829PubMedCrossRefGoogle Scholar
- 16.Hassan T, Timofeev EV, Saito T, Shimizu H, Ezura M, Matsumoto Y, Takayama K, Tominaga T, Takahashi A (2005) A proposed parent vessel geometry-based categorization of saccular intracranial aneurysms: computational flow dynamics analysis of the risk factors for lesion rupture. J Neurosurg 103:662–680PubMedGoogle Scholar
- 17.Spring S, van der Loo B, Krieger E, Amann-Vesti BR, Rousson V, Koppensteiner R (2006) Decreased wall shear stress in the common carotid artery of patients with peripheral arterial disease or abdominal aortic aneurysm: relation to blood rheology, vascular risk factors, and intima-media thickness. J Vasc Surg 43:56–63; discussion 63PubMedCrossRefGoogle Scholar
- 28.Zakaria H, Kallmes D, Ding Y, Lewis D, Robertson AM (2005) Comparison of hemodynamic features of elastase-induced rabbit saccular aneurysms and human aneurysms. In: Proceedings of the Biomedical Engineering Society (BMES), Baltimore, MDGoogle Scholar
- 34.Robertson AM, Sequeira A, Kamaneva M (2007) Blood rheology. In: Galdi GP, Rannacher R, Robertson AM, Turek S (eds) Hemodynamical flows: modeling, analysis and simulation. Birkhauser, BostonGoogle Scholar
- 37.Feldman LJ, Mazighi M, Scheuble A, Deux JF, De Benedetti E, Badier-Commander C, Brambilla E, Henin D, Steg PG, Jacob MP (2001) Differential expression of matrix metalloproteinases after stent implantation and balloon angioplasty in the hypercholesterolemic rabbit. Circulation 103:3117–3122PubMedGoogle Scholar
- 38.Knipp BS, Ailawadi G, Ford JW, Peterson DA, Eagleton MJ, Roelofs KJ, Hannawa KK, Deogracias MP, Ji B, Logsdon C, Graziano KD, Simeone DM, Thompson RW, Henke PK, Stanley JC, Upchurch GR Jr (2004) Increased MMP-9 expression and activity by aortic smooth muscle cells after nitric oxide synthase inhibition is associated with increased nuclear factor-kappaB and activator protein-1 activity. J Surg Res 116:70–80PubMedCrossRefGoogle Scholar