Gene transfer of endothelial nitric oxide synthase alters endothelium-dependent relaxations in aortas from diabetic rabbits.
OBJECTIVE
Cardiovascular disease is the leading cause of death in diabetes mellitus. Abnormal endothelium-dependent relaxation is observed both in humans and in animal models of diabetes mellitus and decreased bioavailability of nitric oxide (NO) is thought to be involved in this defect. Therefore, the aim of this study was to test whether adenovirus-mediated gene transfer of endothelial nitric oxide synthase (eNOS) alters vascular reactivity of diabetic vessels.


METHODS
Vascular reactivity was first assessed in thoracic aortas and carotid arteries from nine alloxan-induced diabetic (plasma glucose, 26.5 +/- 1.2 mmol/l; HbA1c, 6.4 +/- 0.3%) and nine control rabbits (plasma glucose, 11.1 +/- 1.3 mmol/l; HbA1c, 2.1 +/- 0.1%). Vascular reactivity was next examined in thoracic aortas of diabetic animals after ex vivo transduction with replication-deficient adenovirus encoding gene for eNOS (AdeNOS) or beta-galactosidase (Ad beta gal).


RESULTS
After 10 weeks of hyperglycaemia, endothelium-dependent relaxation to acetylcholine was impaired in diabetic aorta, but was normal in carotid arteries from diabetic rabbits. In contrast, responses of both vessels to calcium ionophore and nitric oxide donor were normal. Histochemical staining for beta-galactosidase and immunohistochemistry for eNOS showed transgene expression in the endothelium and adventitia in Ad beta gal and AdeNOS transduced vessels, respectively. During submaximum contractions with phenylephrine, relaxations to low concentrations of acetylcholine (3 x 10(-8) to 10(-7) mol/l) were augmented in AdeNOS transduced diabetic vessels.


CONCLUSIONS
These findings suggest that adenovirus-mediated gene transfer of eNOS to diabetic aorta alters vascular reactivity.
Zanetti
M
M
Department of Endocrinology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Sato
J
J
Katusic
Z S
ZS
O'Brien
T
T
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology / Q000503:physiopathology*; D002339:Carotid Arteries / Q000473:pathology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D066298:In Vitro Techniques; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D011817:Rabbits; D014018:Tissue Distribution; D014664:Vasodilation / Q000502:physiology; D001616:beta-Galactosidase / Q000378:metabolism
D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D001616:beta-Galactosidase