, Volume 49, Issue 12, pp 1041–1053 | Cite as

The influence of hemodynamic forces on biomarkers in the walls of elastase-induced aneurysms in rabbits

  • Ramanathan Kadirvel
  • Yong-Hong Ding
  • Daying Dai
  • Hasballah Zakaria
  • Anne M. Robertson
  • Mark A. Danielson
  • Debra A. Lewis
  • Harry J. Cloft
  • David F. KallmesEmail author
Functional Neuroradiology



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.


Hemodynamics 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.


  1. 1.
    Krex D, Schackert HK, Schackert G (2001) Genesis of cerebral aneurysms – an update. Acta Neurochir (Wien) 143:429–448; discussion 448–429CrossRefGoogle Scholar
  2. 2.
    Stehbens WE (1999) Evaluation of aneurysm models, particularly of the aorta and cerebral arteries. Exp Mol Pathol 67:1–14PubMedCrossRefGoogle Scholar
  3. 3.
    Neil-Dwyer G, Bartlett JR, Nicholls AC, Narcisi P, Pope FM (1983) Collagen deficiency and ruptured cerebral aneurysms. A clinical and biochemical study. J Neurosurg 59:16–20PubMedCrossRefGoogle Scholar
  4. 4.
    Gaetani P, Tartara F, Tancioni F, Rodriguez y Baena R, Casari E, Alfano M, Grazioli V (1997) Deficiency of total collagen content and of deoxypyridinoline in intracranial aneurysm walls. FEBS Lett 404:303–306PubMedCrossRefGoogle Scholar
  5. 5.
    Sugai M, Shoji M (1968) Pathogenesis of so-called congenital aneurysms of the brain. Acta Pathol Jpn 18:139–160PubMedGoogle Scholar
  6. 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
  7. 7.
    Shojima M, Oshima M, Takagi K, Torii R, Hayakawa M, Katada K, Morita A, Kirino T (2004) Magnitude and role of wall shear stress on cerebral aneurysm: computational fluid dynamic study of 20 middle cerebral artery aneurysms. Stroke 35:2500–2505PubMedCrossRefGoogle Scholar
  8. 8.
    Malek AM, Alper SL, Izumo S (1999) Hemodynamic shear stress and its role in atherosclerosis. JAMA 282:2035–2042PubMedCrossRefGoogle Scholar
  9. 9.
    Woessner JF Jr (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5:2145–2154PubMedGoogle Scholar
  10. 10.
    Kuzuya M, Iguchi A (2003) Role of matrix metalloproteinases in vascular remodeling. J Atheroscler Thromb 10:275–282PubMedGoogle Scholar
  11. 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
  12. 12.
    Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT (2002) Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 110:625–632PubMedCrossRefGoogle Scholar
  13. 13.
    Chua PK, Melish ME, Yu Q, Yanagihara R, Yamamoto KS, Nerurkar VR (2003) Elevated levels of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 during the acute phase of Kawasaki disease. Clin Diagn Lab Immunol 10:308–314PubMedCrossRefGoogle Scholar
  14. 14.
    Bruno G, Todor R, Lewis I, Chyatte D (1998) Vascular extracellular matrix remodeling in cerebral aneurysms. J Neurosurg 89:431–440PubMedGoogle Scholar
  15. 15.
    Kim SC, Singh M, Huang J, Prestigiacomo CJ, Winfree CJ, Solomon RA, Connolly ES Jr (1997) Matrix metalloproteinase-9 in cerebral aneurysms. Neurosurgery 41:642–666; discussion 646–647PubMedCrossRefGoogle Scholar
  16. 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. 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
  18. 18.
    Meng H, Swartz DD, Wang Z, Hoi Y, Kolega J, Metaxa EM, Szymanski MP, Yamamoto J, Sauvageau E, Levy EI (2006) A model system for mapping vascular responses to complex hemodynamics at arterial bifurcations in vivo. Neurosurgery 59:1094–1100; discussion 1100–1091PubMedCrossRefGoogle Scholar
  19. 19.
    Dimmeler S, Haendeler J, Rippmann V, Nehls M, Zeiher AM (1996) Shear stress inhibits apoptosis of human endothelial cells. FEBS Lett 399:71–74PubMedCrossRefGoogle Scholar
  20. 20.
    Dewey CF Jr, Bussolari SR, Gimbrone MA Jr, Davies PF (1981) The dynamic response of vascular endothelial cells to fluid shear stress. J Biomech Eng 103:177–185PubMedGoogle Scholar
  21. 21.
    Sakamoto N, Ohashi T, Sato M (2006) Effect of fluid shear stress on migration of vascular smooth muscle cells in cocultured model. Ann Biomed Eng 34:408–415CrossRefGoogle Scholar
  22. 22.
    Vyalov S, Langille BL, Gotlieb AI (1996) Decreased blood flow rate disrupts endothelial repair in vivo. Am J Pathol 149:2107–2118PubMedGoogle Scholar
  23. 23.
    Sun HB, Smith GN Jr, Hasty KA, Yokota H (2000) Atomic force microscopy-based detection of binding and cleavage site of matrix metalloproteinase on individual type II collagen helices. Anal Biochem 283:153–158PubMedCrossRefGoogle Scholar
  24. 24.
    Allaire E, Forough R, Clowes M, Starcher B, Clowes AW (1998) Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model. J Clin Invest 102:1413–1420PubMedCrossRefGoogle Scholar
  25. 25.
    Allaire E, Muscatelli-Groux B, Mandet C, Guinault AM, Bruneval P, Desgranges P, Clowes A, Melliere D, Becquemin JP (2002) Paracrine effect of vascular smooth muscle cells in the prevention of aortic aneurysm formation. J Vasc Surg 36:1018–1026PubMedCrossRefGoogle Scholar
  26. 26.
    Ailawadi G, Knipp BS, Lu G, Roelofs KJ, Ford JW, Hannawa KK, Bishop K, Thanaporn P, Henke PK, Stanley JC, Upchurch GR Jr (2003) A nonintrinsic regional basis for increased infrarenal aortic MMP-9 expression and activity. J Vasc Surg 37:1059–1066PubMedCrossRefGoogle Scholar
  27. 27.
    Short JG, Fujiwara NH, Marx WF, Helm GA, Cloft HJ, Kallmes DF (2001) Elastase-induced saccular aneurysms in rabbits: comparison of geometric features with those of human aneurysms. AJNR Am J Neuroradiol 22:1833–1837PubMedGoogle Scholar
  28. 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
  29. 29.
    Kallmes DF, Fujiwara NH, Yuen D, Dai D, Li ST (2003) A collagen-based coil for embolization of saccular aneurysms in a New Zealand White rabbit model. AJNR Am J Neuroradiol 24:591–596PubMedGoogle Scholar
  30. 30.
    Zakaria H, Kallmes D, Kadirvel R, Ding Y, Dai D, Lewis D, Robertson A (2006) Similar hemodynamic features in elastase-induced rabbit saccular aneurysms compared to those of human aneurysms. J Biomech 39:S366CrossRefGoogle Scholar
  31. 31.
    Heywood JG, Rannacher R, Turek S (1996) Artificial boundaries and flux and pressure conditions for the incompressible Navier-Stokes equations. Int J Num Method Fluids 22:325–352CrossRefGoogle Scholar
  32. 32.
    Cebral JR, Castro MA, Burgess JE, Pergolizzi RS, Sheridan MJ, Putman CM (2005) Characterization of cerebral aneurysms for assessing risk of rupture by using patient-specific computational hemodynamics models. AJNR Am J Neuroradiol 26:2550–2559PubMedGoogle Scholar
  33. 33.
    Steinman DA, Milner JS, Norley CJ, Lownie SP, Holdsworth DW (2003) Image-based computational simulation of flow dynamics in a giant intracranial aneurysm. AJNR Am J Neuroradiol 24:559–566PubMedGoogle Scholar
  34. 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
  35. 35.
    Berceli SA, Jiang Z, Klingman NV, Pfahnl CL, Abouhamze ZS, Frase CD, Schultz GS, Ozaki CK (2004) Differential expression and activity of matrix metalloproteinases during flow-modulated vein graft remodeling. J Vasc Surg 39:1084–1090PubMedCrossRefGoogle Scholar
  36. 36.
    AAssar OS, Fujiwara NH, Marx WF, Matsumoto AH, Kallmes DF (2003) Aneurysm growth, elastinolysis, and attempted doxycycline inhibition of elastase-induced aneurysms in rabbits. J Vasc Interv Radiol 14:1427–1432PubMedGoogle Scholar
  37. 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. 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

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Ramanathan Kadirvel
    • 1
  • Yong-Hong Ding
    • 1
  • Daying Dai
    • 1
  • Hasballah Zakaria
    • 2
  • Anne M. Robertson
    • 2
  • Mark A. Danielson
    • 1
  • Debra A. Lewis
    • 1
  • Harry J. Cloft
    • 1
  • David F. Kallmes
    • 1
    Email author
  1. 1.Department of RadiologyMayo Clinic College of MedicineRochesterUSA
  2. 2.Department of Mechanical EngineeringUniversity of PittsburghPittsburghUSA

Personalised recommendations