The transgenic arteriovenous fistula in the rat: an experimental model of gene therapy for brain arteriovenous malformations.
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 beta-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, beta-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 beta-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.


CONCLUSIONS
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.
Lawton
Michael T
MT
Department of Neurological Surgery, Center for Cerebrovascular Research, University of California, San Francisco, 94143-0012, USA. lawtonm@neurosurg.ucsf.edu
Stewart
Campbell L
CL
Wulfstat
Amanda A
AA
Derugin
Nikita
N
Hashimoto
Tomoki
T
Young
William L
WL
D000818:Animals; D001011:Aorta / Q000637:transplantation; D001166:Arteriovenous Shunt, Surgical / Q000379:methods*; D017536:Carotid Artery, Common / Q000601:surgery; D004195:Disease Models, Animal; D005240:Feasibility Studies; D015870:Gene Expression; D017930:Genes, Reporter; D015316:Genetic Therapy; D006085:Graft Survival; D002538:Intracranial Arteriovenous Malformations / Q000628:therapy; D007601:Jugular Veins / Q000601:surgery; D051379:Mice; D051381:Rats; D011923:Rats, Nude; D013997:Time Factors; D014654:Vascular Patency