In vivo gene transfer of endothelial nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits enhances endothelium-dependent relaxations.
OBJECTIVE
Hypercholesterolemia is associated with abnormal endothelium-dependent vasorelaxation due to decreased nitric oxide bioavailability. Our aim was to examine the effect of adenovirus-mediated gene transfer of endothelial nitric oxide synthase (eNOS) to the hypercholesterolemic rabbit carotid artery in vivo. In addition, we examined whether adenovirus-mediated gene transfer was associated with vascular dysfunction.


METHODS
Rabbits were fed a 1% cholesterol diet for 4 weeks followed by a 0.5% cholesterol diet for 6 weeks. Vascular reactivity was assessed in nontransduced carotid arteries from chow- and cholesterol-fed animals. In addition, carotid arteries were surgically isolated, and 2 separate doses of adenoviral vectors encoding eNOS or beta-galactosidase (AdbetaGal) on the contralateral side were delivered to the lumen (1x10(10) and 5x10(10) pfu/mL).


RESULTS
Abnormal acetylcholine-mediated endothelium-dependent vasorelaxation was detected in the carotid artery from cholesterol-fed animals, whereas responses to calcium ionophore A23187 and diethylamine NONOate were normal. Vascular reactivity was similar in nontransduced and AdbetaGal-transduced hypercholesterolemic vessels. In vessels transduced with eNOS, transgene expression was demonstrated by immunostaining in both the endothelium and the adventitia and by Western blot analysis. High-dose but not low-dose eNOS gene transfer enhanced endothelium-dependent relaxation in vessels from cholesterol-fed rabbits.


CONCLUSIONS
Adenovirus-mediated gene transfer of eNOS to carotid arteries of cholesterol-fed animals improves endothelium-dependent relaxation when an optimal viral titer is administered.
Sato
J
J
Departments of Endocrinology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Mohácsi
T
T
Noel
A
A
Jost
C
C
Gloviczki
P
P
Mozes
G
G
Katusic
Z S
ZS
O'Brien
T
T
Mayhan
W G
WG
D000818:Animals; D002339:Carotid Arteries / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D018014:Gene Transfer Techniques; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D008055:Lipids / Q000097:blood; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011817:Rabbits; D014018:Tissue Distribution; D014664:Vasodilation; D014666:Vasomotor System / Q000503:physiopathology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D008055:Lipids; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D001616:beta-Galactosidase