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

Circ Res. 2003 Oct 3;93(7):622-9. doi: 10.1161/01.RES.0000092140.81594.A8. Epub 2003 Aug 21.


The bioavailability of nitric oxide (NO) within the vascular wall is limited by superoxide anions (O2.-). The relevance of extracellular superoxide dismutase (ecSOD) for the detoxification of vascular O2.- 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 O2.-, 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 O2.-, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Angiotensin II / administration & dosage
  • Animals
  • Blood Pressure / drug effects
  • Blotting, Western
  • Catalase / pharmacology
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / physiology
  • Endothelium, Vascular / physiopathology
  • Female
  • Humans
  • Hypertension / chemically induced
  • Hypertension / metabolism
  • Hypertension / physiopathology
  • Hypertension, Renovascular / metabolism
  • Hypertension, Renovascular / physiopathology
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Knockout
  • Nitric Oxide / metabolism*
  • Nitroprusside / pharmacology
  • Phenylephrine / pharmacology
  • Recombinant Proteins / pharmacology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase / pharmacology*
  • Superoxides / metabolism
  • Vasoconstrictor Agents / pharmacology
  • Vasodilation / drug effects
  • Vasodilator Agents / pharmacology


  • Recombinant Proteins
  • Vasoconstrictor Agents
  • Vasodilator Agents
  • Superoxides
  • Angiotensin II
  • Nitroprusside
  • Phenylephrine
  • Nitric Oxide
  • Catalase
  • Superoxide Dismutase
  • Acetylcholine