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Increased gene expression in densely packed aneurysms was associated with adhesion molecules, proteases, and cytokines in the rabbit aneurysm model; loosely packed aneurysms showed increased expression of multiple structural molecules, including collagens.


To compare gene expression patterns between well-healed and poorly healed aneurysms following coil embolization in a rabbit model.

Materials and Methods

The Institutional Animal Care and Use Committee approved all procedures before initiation of the study. Elastase-induced, saccular aneurysms were created in rabbits and embolized by using platinum microcoils. Group 1 aneurysms were densely packed (volumetric packing density, >30%) to achieve good healing, whereas group 2 aneurysms were loosely packed (volumetric packing density, <20%), which yields poor healing. At 2 or 4 weeks after implantation, samples were harvested. RNA was isolated separately from the necks and domes of the aneurysms and analyzed by using a microarray containing 294 rabbit genes. Genes with significant differences between groups (P < .05; false discovery rate, <0.1; fold change, ≥1.2 and ≤0.8) were considered differentially expressed.


At 2 weeks, of 294 genes, 22 (7.5%) genes in the neck and 14 (4.8%) genes in the dome were differentially expressed between groups; at 4 weeks, of 294 genes, 25 (8.5%) genes in the neck and 17 (5.8%) genes in the dome were differentially expressed between groups. Genes overexpressed in group 1 as compared with group 2 aneurysms included those encoding proteases, adhesion molecules, and chemoattractant molecules. Conversely, group 2 aneurysms had increased expression of genes encoding structural molecules, including collagens, as compared with expression in group 1 aneurysms.


Robust healing after coil embolization is associated with substantial biological activity, as evidenced by overexpression of proteases, adhesion molecules, and chemoattractants. However, contrary to prior hypotheses, structural molecules such as collagen were not associated with the healing response in the rabbit model.

© RSNA, 2010


  • 1 Guglielmi G, Viñuela F, Dion J, Duckwiler G. Electrothrombosis of saccular aneurysms via endovascular approach. II. Preliminary clinical experience. J Neurosurg 1991;75(1):8–14. Crossref, MedlineGoogle Scholar
  • 2 Ferns SP, Sprengers ME, van Rooij WJ, et al.. Coiling of intracranial aneurysms: a systematic review on initial occlusion and reopening and retreatment rates. Stroke 2009;40(8):e523–e529. Google Scholar
  • 3 Gallas S, Januel AC, Pasco A, et al.. Long-term follow-up of 1036 cerebral aneurysms treated by bare coils: a multicentric cohort treated between 1998 and 2003. AJNR Am J Neuroradiol 2009;30(10):1986–1992. Crossref, MedlineGoogle Scholar
  • 4 Whitlow CT, Geer CP, Mattern CW, et al.. Endovascular histologic effects of ultrathin gold- or vitronectin-coated platinum aneurysm coils in a rodent arterial occlusion model: a preliminary investigation. AJNR Am J Neuroradiol 2009;30(1):85–90. Crossref, MedlineGoogle Scholar
  • 5 van Rooij WJ, de Gast AN, Sluzewski M. Results of 101 aneurysms treated with polyglycolic/polylactic acid microfilament nexus coils compared with historical controls treated with standard coils. AJNR Am J Neuroradiol 2008;29(5):991–996. Crossref, MedlineGoogle Scholar
  • 6 Dai D, Ding YH, Danielson MA, et al.. Endovascular treatment of experimental aneurysms by use of fibroblast-coated platinum coils: an angiographic and histopathologic study. Stroke 2007;38(1):170–176. Crossref, MedlineGoogle Scholar
  • 7 Dai D, Ding YH, Danielson MA, et al.. Endovascular treatment of experimental aneurysms with use of fibroblast transfected with replication-deficient adenovirus containing bone morphogenetic protein-13 gene. AJNR Am J Neuroradiol 2008;29(4):739–744. Crossref, MedlineGoogle Scholar
  • 8 Dai D, Ding YH, Danielson MA, et al.. Histopathologic and immunohistochemical comparison of human, rabbit, and swine aneurysms embolized with platinum coils. AJNR Am J Neuroradiol 2005;26(10):2560–2568. MedlineGoogle Scholar
  • 9 Szikora I, Seifert P, Hanzely Z, et al.. Histopathologic evaluation of aneurysms treated with Guglielmi detachable coils or matrix detachable microcoils. AJNR Am J Neuroradiol 2006;27(2):283–288. MedlineGoogle Scholar
  • 10 Gunnarsson T, Tong FC, Klurfan P, Cawley CM, Dion JE. Angiographic and clinical outcomes in 200 consecutive patients with cerebral aneurysm treated with hydrogel-coated coils. AJNR Am J Neuroradiol 2009;30(9):1657–1664. Crossref, MedlineGoogle Scholar
  • 11 Linfante I, DeLeo MJ, Gounis MJ, Gounis MJ, Brooks CS, Wakhloo AK. Cerecyte versus platinum coils in the treatment of intracranial aneurysms: packing attenuation and clinical and angiographic midterm results. AJNR Am J Neuroradiol 2009;30(8):1496–1501. Crossref, MedlineGoogle Scholar
  • 12 Piotin M, Spelle L, Mounayer C, Loureiros C, Ghorbani A, Moret J. Intracranial aneurysms coiling with matrix: immediate results in 152 patients and midterm anatomic follow-up from 115 patients. Stroke 2009;40(1):321–323. Crossref, MedlineGoogle Scholar
  • 13 Ding YH, Dai D, Kadirvel R, Lewis DA, Cloft HJ, Kallmes DF. Relationship between aneurysm volume and histologic healing after coil embolization in elastase-induced aneurysms: a retrospective study. AJNR Am J Neuroradiol 2008;29(1):98–101. Crossref, MedlineGoogle Scholar
  • 14 Sluzewski M, van Rooij WJ, Slob MJ, Bescós JO, Slump CH, Wijnalda D. Relation between aneurysm volume, packing, and compaction in 145 cerebral aneurysms treated with coils. Radiology 2004;231(3):653–658. LinkGoogle Scholar
  • 15 Kadirvel R, Ding YH, Dai D, Lewis DA, Kallmes DF. Differential expression of genes in elastase-induced saccular aneurysms with high and low aspect ratios. Neurosurgery 2010;66(3):578–584; discussion 584. Crossref, MedlineGoogle Scholar
  • 16 Mangrum WI, Farassati F, Kadirvel R, et al.. mRNA expression in rabbit experimental aneurysms: a study using gene chip microarrays. AJNR Am J Neuroradiol 2007;28(5):864–869. MedlineGoogle Scholar
  • 17 Altes TA, Cloft HJ, Short JG, et al.; American Roentgen Ray Society. 1999 ARRS Executive Council Award. Creation of saccular aneurysms in the rabbit: a model suitable for testing endovascular devices. AJR Am J Roentgenol 2000;174(2):349–354. Crossref, MedlineGoogle Scholar
  • 18 Kallmes DF, Helm GA, Hudson SB, et al.. Histologic evaluation of platinum coil embolization in an aneurysm model in rabbits. Radiology 1999;213(1):217–222. LinkGoogle Scholar
  • 19 Wakhloo AK, Gounis MJ, Sandhu JS, Akkawi N, Schenck AE, Linfante I. Complex-shaped platinum coils for brain aneurysms: higher packing density, improved biomechanical stability, and midterm angiographic outcome. AJNR Am J Neuroradiol 2007;28(7):1395–1400. Crossref, MedlineGoogle Scholar
  • 20 Dai D, Ding YH, Danielson MA, et al.. Modified histologic technique for processing metallic coil-bearing tissue. AJNR Am J Neuroradiol 2005;26(8):1932–1936. MedlineGoogle Scholar
  • 21 Ding YH, Dai D, Lewis DA, Cloft HJ, Kallmes DF. Angiographic and histologic analysis of experimental aneurysms embolized with platinum coils, Matrix, and HydroCoil. AJNR Am J Neuroradiol 2005;26(7):1757–1763. MedlineGoogle Scholar
  • 22 Dai D, Ding YH, Lewis DA, Kallmes DF. A proposed ordinal scale for grading histology in elastase-induced, saccular aneurysms. AJNR Am J Neuroradiol 2006;27(1):132–138. MedlineGoogle Scholar
  • 23 Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 2000;132:365–386. MedlineGoogle Scholar
  • 24 Eckel JE, Gennings C, Therneau TM, Burgoon LD, Boverhof DR, Zacharewski TR. Normalization of two-channel microarray experiments: a semiparametric approach. Bioinformatics 2005;21(7):1078–1083. Crossref, MedlineGoogle Scholar
  • 25 Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc, B 1995;57:289–300. Google Scholar
  • 26 Dawson RC, Krisht AF, Barrow DL, Joseph GJ, Shengelaia GG, Bonner G. Treatment of experimental aneurysms using collagen-coated microcoils. Neurosurgery 1995;36(1):133–139; discussion 139–140. Crossref, MedlineGoogle Scholar
  • 27 Ribourtout E, Desfaits AC, Salazkin I, Raymond J. Ex vivo gene therapy with adenovirus-mediated transforming growth factor beta1 expression for endovascular treatment of aneurysm: results in a canine bilateral aneurysm model. J Vasc Surg 2003;38(3):576–583. Crossref, MedlineGoogle Scholar
  • 28 Dai D, Ding YH, Kadirvel R, et al.. A longitudinal immunohistochemical study of the healing of experimental aneurysms after embolization with platinum coils. AJNR Am J Neuroradiol 2006;27(4):736–741. MedlineGoogle Scholar
  • 29 Klebe RJ, Rosenberger PG, Naylor SL, Burns RL, Novak R, Kleinman H. Cell attachment to collagen: isolation of a cell attachment mutant. Exp Cell Res 1977;104(1):119–125. Crossref, MedlineGoogle Scholar
  • 30 McCarthy JB, Vachhani B, Iida J. Cell adhesion to collagenous matrices. Biopolymers 1996;40(4):371–381. Crossref, MedlineGoogle Scholar
  • 31 Liaw L, Birk DE, Ballas CB, Whitsitt JS, Davidson JM, Hogan BL. Altered wound healing in mice lacking a functional osteopontin gene (spp1). J Clin Invest 1998;101(7):1468–1478. Crossref, MedlineGoogle Scholar
  • 32 Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM. Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. Circ Res 1994;74(2):214–224. Crossref, MedlineGoogle Scholar
  • 33 Burdo TH, Wood MR, Fox HS. Osteopontin prevents monocyte recirculation and apoptosis. J Leukoc Biol 2007;81(6):1504–1511. Crossref, MedlineGoogle Scholar
  • 34 Denhardt DT, Noda M, O’Regan AW, Pavlin D, Berman JS. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 2001;107(9):1055–1061. Crossref, MedlineGoogle Scholar
  • 35 Jin D, Sheng J, Yang X, Gao B.. Matrix metalloproteinases and tissue inhibitors of metalloproteinases expression in human cerebral ruptured and unruptured aneurysm. Surg Neurol 2007; 68 (suppl 2):S11–16; discussion S16. Google Scholar
  • 36 Bouzeghrane F, Darsaut T, Salazkin I, Ogoudikpe C, Gevry G, Raymond J. Matrix metalloproteinase-9 may play a role in recanalization and recurrence after therapeutic embolization of aneurysms or arteries. J Vasc Interv Radiol 2007;18(10):1271–1279. Crossref, MedlineGoogle Scholar
  • 37 Cho A, Reidy MA. Matrix metalloproteinase-9 is necessary for the regulation of smooth muscle cell replication and migration after arterial injury. Circ Res 2002;91(9):845–851. Crossref, MedlineGoogle Scholar
  • 38 Galis ZS, Johnson C, Godin D, et al.. Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ Res 2002;91(9):852–859. Crossref, MedlineGoogle Scholar
  • 39 Prall AK, Longo GM, Mayhan WG, et al.. Doxycycline in patients with abdominal aortic aneurysms and in mice: comparison of serum levels and effect on aneurysm growth in mice. J Vasc Surg 2002;35(5):923–929. Crossref, MedlineGoogle Scholar
  • 40 Guessous I, Periard D, Lorenzetti D, Cornuz J, Ghali WA. The efficacy of pharmacotherapy for decreasing the expansion rate of abdominal aortic aneurysms: a systematic review and meta-analysis. PLoS One 2008; 3:1–10. Accessed 2010. CrossrefGoogle Scholar

Article History

Received February 15, 2010; revision requested April 29; final revision received May 18; accepted May 27; final version accepted June 8.
Published online: Nov 2010
Published in print: Nov 2010