The transgenic arteriovenous fistula in the rat: An experimental model of gene therapy for brain arteriovenous malformations

Michael T. Lawton, Campbell L. Stewart, Amanda A. Wulfstat, Nikita Derugin, Tomoki Hashimoto, William L. Young, Ralph G. Dacey, Warren R. Selman, J. Max Findlay, David A. Omahen

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

OBJECTIVE: To introduce the transgenic arteriovenous fistula model in the rat, constructed by interposing mouse aorta in a fistula between the common carotid artery and external jugular vein in a nude rat, and to describe the model's technical feasibility, long-term patency, and expression of reporter genes. METHODS: Carotid-jugular fistulae were surgically created in 112 rats. In 25 immunodeficient nude rats, wild-type mouse thoracic aorta (TAo) was interposed in the fistula; in 10 immunocompetent rats, TAo was interposed; in 19 nude rats, transgenic TAo with reporter genes for β-galactosidase or, green fluorescent protein was interposed; in 18 nude rats, wild-type mouse ascending aorta was interposed; and in 40 rats, a simple fistula was constructed without an interpositional graft. Host tolerance and graft viability were analyzed by histopathology and immunohistochemistry for CD31 (mouse endothelial cell marker), endothelial nitric oxide synthase, smooth muscle actin, fibronectin, β-galactosidase, and green fluorescent protein. RESULTS: The transgenic arteriovenous fistula was technically feasible and immunologically tolerated in nude rats but not in immunocompetent rats. The overall angiographic patency rate was 41% with TAo grafts and 56% with ascending aorta grafts, both lower than the 98% patency rate in fistulae with a single anastomosis and no interpositional graft. Mouse endothelium survived on the graft for 3 months according to CD31 staining, but longer survival by transgenic smooth muscle cells resulted in continued expression of β-galactosidase for 6 months and green fluorescent protein for 4 months. Endothelium and smooth muscle in the fistula were functional, with normal expression of endothelial nitric oxide synthase as well as smooth muscle actin and fibronectin, respectively. CONCLUSION: The transgenic arteriovenous fistula model enhances other carotid-jugular fistula models by integrating transgenic tissue, thereby creating an experimental system for investigating the molecular biology of and gene therapies for arteriovenous malformations.

Original languageEnglish
Pages (from-to)1463-1471
Number of pages9
JournalNeurosurgery
Volume54
Issue number6
DOIs
StatePublished - Jun 2004

Keywords

  • Anastomosis
  • Brain arteriovenous malformation
  • Fistula
  • Gene therapy
  • Nude rat
  • Transgenic mouse

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