Extracellular superoxide dismutase is a major determinant of nitric oxide bioavailability: in vivo and ex vivo evidence from ecSOD-deficient mice

The bioavailability of nitric oxide (NO) within the vascular wall is limited by superoxide anions (O 2 ·− ). The relevance of extracellular superoxide dismutase (ecSOD) for the detoxification of vascular O 2 ·− is unknown. We determined the involvement of ecSOD in the control of blood pressure and endothelium-dependent responses in angiotensin II–induced hypertension and renovascular hypertension induced by the two-kidney, one-clip model in wild-type mice and mice lacking the ecSOD gene. Blood pressure was identical in sham-operated ecSOD +/+ and ecSOD −/− mice. After 6 days of angiotensin II–treatment and 2 and 4 weeks after renal artery clipping, blood pressure was significantly higher in ecSOD −/− than ecSOD +/+ mice. Recombinant ecSOD selectively decreased blood pressure in hypertensive ecSOD −/− mice, whereas ecSOD had no effect in normotensive and hypertensive ecSOD +/+ mice. Compared with sham-operated ecSOD +/+ mice, sham-operated ecSOD −/− mice exhibited attenuated acetylcholine-induced relaxations. These responses were further depressed in vessels from clipped animals. Vascular O 2 ·− , as measured by lucigenin chemiluminescence, was higher in ecSOD −/− compared with ecSOD +/+ mice and was increased by clipping. The antioxidant tiron normalized relaxations in vessels from sham-operated and clipped ecSOD −/− , as well as from clipped ecSOD +/+ mice. In contrast, in vivo application of ecSOD selectively enhanced endothelium-dependent relaxation in vessels from ecSOD −/− mice. These data reveal that endogenous ecSOD is a major antagonistic principle to vascular O 2 ·− , controlling blood pressure and vascular function in angiotensin II–dependent models of hypertension. ecSOD is expressed in such an abundance that even in situations of high oxidative stress no relative lack of enzyme activity occurs.