Gene transfer of manganese superoxide dismutase reverses vascular dysfunction in the absence but not in the presence of atherosclerotic plaque

Impaired endothelium-dependent vasorelaxation (EDVR) is observed in hyperch olesterolemia both in the presence and absence of morphological abnormaliti es and may be due to superoxide anions. Our aim was to assess the effect of gene transfer of manganese superoxide dismutase (MnSOD) to blood vessels f rom hypercholesterolemic animals with and without atherosclerotic plaque an d to compare the effects of endothelial nitric oxide synthase (eNOS) and Mn SOD over-expression on vascular dysfunction in the setting of atheroscleros is. Rabbits received a high-cholesterol diet for 10 weeks, resulting in abn ormal EDVR in the absence of plaque in the carotids and the presence of pla que in the aorta. In Group 1, adenoviral vectors encoding MnSOD (Ad MnSOD) or beta -galactosidase (Ad beta gal) were delivered to the carotid arteries in vivo. Four days later, transgene expression and vascular reactivity wer e assessed. In Group 2, segments of the aorta were transduced ex vivo with AdMnSOD, AdeNOS or both. Transgene expression and vascular reactivity were assessed 24 hr later. In Group 1, MnSOD expression was detected in AdMnSOD- ransduced vessels and impaired EDVR was reversed in the absence of atherosc lerotic plaque. In Group 2 (with atherosclerotic plaque present), MnSOD and eNOS expression were detected by western analysis, and eNOS, but not MnSOD over-expression, improved EDVR whereas simultaneous over-expression of eNO S and MnSOD was no better than eNOS alone. Adenovirus-mediated gene transfe r of MnSOD to nonatherosclerotic carotid arteries, but not atherosclerotic aorta, normalizes EDVR. eNOS gene transfer improves EDVR, even in the prese nce of plaque.