From the Departments of Anesthesiology and Pharmacology and Division of
Endocrinology and Metabolism (T. O'B.), Mayo Medical Center, Rochester,
Minn.
Correspondence to Zvonimir S. Katusic, MD, PhD, Departments of Anesthesiology and Pharmacology, Mayo Medical Center, 200 First St SW, Rochester, MN 55905. E-mail katusic.zvonimir{at}mayo.edu
Background and Purpose—Gene transfer
with recombinant viral vectors encoding vasodilator proteins may be
useful in therapy of cerebral vasospasm after subarachnoid
hemorrhage (SAH). Relaxations mediated by nitric oxide are
impaired in cerebral arteries affected by SAH. The present study
was designed to determine the effect of SAH on the efficiency of ex
vivo adenovirus-mediated gene transfer to canine basilar arteries and
to examine whether expression of recombinant
endothelial nitric oxide synthase (eNOS) gene may have
functional effects on vasomotor reactivity of spastic arteries affected
by SAH.
Methods—Replication-deficient recombinant adenovirus vectors
encoding bovine eNOS (AdCMVeNOS) and Escherichia coli
ß-galactosidase (AdCMVß-Gal) genes were used for ex vivo gene
transfer. Rings of basilar arteries obtained from control dogs and dogs
exposed to SAH were incubated with the vectors in minimum essential
medium. Twenty-four hours after gene transfer, expression and function
of the recombinant genes were evaluated by (1) histochemical or
immunohistochemical staining, (2) ß-galactosidase protein
measurement, and (3) isometric tension recording.
Results—Transduction with AdCMVß-Gal and AdCMVeNOS resulted in
the expression of recombinant ß-galactosidase and eNOS proteins
mostly in the vascular adventitia. The expression of ß-galactosidase
protein was
Conclusions—These results suggest that expression of recombinant
proteins after adenovirus-mediated gene transfer may be enhanced in
cerebral arteries affected by SAH and that successful eNOS gene
transfer to spastic arteries can at least partly restore the impaired
nitric oxide–mediated relaxations through local (adventitial)
production of nitric oxide.
Department
of Internal Medicine Cardiovascular
Division University of Iowa College of Medicine Iowa City, Iowa
© 1998 American Heart Association, Inc.
Original Contributions
Expression and Function of Recombinant Endothelial Nitric Oxide Synthase Gene in Canine Basilar Artery After Experimental Subarachnoid Hemorrhage
2-fold higher in SAH arteries than in normal arteries.
Endothelium-dependent relaxations caused by bradykinin
and substance P were suppressed in SAH arteries. The relaxations to
bradykinin were significantly augmented in both normal and SAH arteries
after AdCMVeNOS transduction but not after AdCMVß-Gal transduction.
The relaxations to substance P were augmented by AdCMVeNOS transduction
only in normal arteries. Bradykinin and substance P caused relaxations
even in endothelium-denuded arteries, when the vessels
were transduced with AdCMVeNOS. These
endothelium-independent (adventitia-dependent)
relaxations to bradykinin observed after AdCMVeNOS transduction were
similar between normal and SAH arteries, whereas those to substance P
were significantly reduced in SAH arteries compared with normal
arteries.
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