Impairment of dilator responses of cerebral arterioles during diabetes mellitus: role of inducible NO synthase.

Background And Purpose: During diabetes, expression of inducible nitric oxide synthase (iNOS) plays an important role in the development of endothelial dysfunction in extracranial blood vessels. Progression of vascular dysfunction after the onset of diabetes differs among vascular beds. In this study, the effects of hyperglycemia/diabetes on vasomotor function were examined in cerebral arterioles at 2 different times in control and iNOS-deficient mice and compared with the effects on carotid arteries.

Vascular interleukin-10 protects against LPS-induced vasomotor dysfunction.

We tested the hypotheses that 1) systemic IL-10, after adenoviral gene transfer, protects arteries from impaired relaxation produced by LPS; 2) local expression of IL-10 within the arterial wall protects against vasomotor dysfunction after LPS; and 3) IL-10 protects against vascular dysfunction mediated by inducible NO synthase (iNOS) after LPS. In IL-10-deficient (IL-10-/-) and wild-type (WT, IL-10+/+) mice, LPS in vivo impaired relaxation of arteries to acetylcholine and gene transfer of IL-10 improved responses to acetylcholine. Superoxide levels were elevated in arteries after LPS, and increased levels of superoxide were prevented by gene transfer of IL-10.

Gene transfer of extracellular superoxide dismutase improves endothelial function in rats with heart failure.

Oxidative stress is associated with endothelial dysfunction in heart failure. The goals of this study were to determine whether 1) gene transfer of extracellular superoxide dismutase (ecSOD) reduces levels of superoxide and improves endothelial function in the aorta and mesenteric artery in rats with heart failure, and 2) the heparin-binding domain (HBD) of ecSOD, by which ecSOD binds to cells, is required for protective effects of ecSOD. Seven weeks after coronary ligation, in rats with heart failure and sham-operated rats, we injected adenoviral vectors intravenously that express ecSOD, ecSOD with deletion of the HBD (ecSODDeltaHBD), or a control vector.

Mechanisms of inducible nitric oxide synthase-mediated vascular dysfunction.

Objective: Inducible nitric oxide synthase (iNOS) is expressed in arteries during inflammation and may contribute to vascular dysfunction. Effects of gene transfer of iNOS to carotid arteries were examined in vitro in the absence of systemic inflammation to allow examination of mechanisms by which iNOS impairs contraction and relaxation.

Methods And Results: After gene transfer of iNOS with an adenovirus (AdiNOS), constrictor responses to phenylephrine (PE) and U46619 were impaired.

Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin.

Lipopolysaccharide (LPS) impairs vascular function, in part by generation of reactive oxygen species. One goal of this study was to determine whether gene transfer of extracellular SOD (ECSOD) improves vascular responsiveness in LPS-treated rats. A second goal was to determine whether effects of ECSOD are dependent on the heparin-binding domain of the enzyme, which facilitates binding of ECSOD to the outside of cells.