Erythropoietin increases bioavailability of tetrahydrobiopterin and protects cerebral microvasculature against oxidative stress induced by eNOS uncoupling
Article first published online: 6 AUG 2014
© 2014 International Society for Neurochemistry
Journal of Neurochemistry
Volume 131, Issue 4, pages 521–529, November 2014
How to Cite
J. Neurochem. (2014) 131, 521–529.
- Issue published online: 4 NOV 2014
- Article first published online: 6 AUG 2014
- Accepted manuscript online: 18 JUL 2014 10:33AM EST
- Manuscript Accepted: 15 JUL 2014
- Manuscript Revised: 9 JUL 2014
- Manuscript Received: 5 JUN 2014
- National Institutes of Health
- Roche Foundation for Anemia Research
- Mayo Foundation. Grant Numbers: HL 91867, HL111062
- cerebral microvessels;
- GTP cyclohydrolase I;
- hph1 mice;
- nitric oxide;
This study was designed to determine whether treatment with erythropoietin (EPO) could protect cerebral microvasculature against the pathological consequences of endothelial nitric oxide (NO) synthase uncoupling. Wild-type and GTP cyclohydrolase I (GTPCH-I)-deficient hph1 mice were administered EPO (1000 U/kg/day, s.c., 3 days). Cerebral microvessels of hph1 mice demonstrated reduced tetrahydrobiopterin (BH4) bioavailability, increased production of superoxide anions and impaired endothelial NO signaling. Treatment of hph1 mice with EPO attenuated the levels of 7,8-dihydrobiopterin, the oxidized product of BH4, and significantly increased the ratio of BH4 to 7,8-dihydrobiopterin. Moreover, EPO decreased the levels of superoxide anions and increased NO bioavailability in cerebral microvessels of hph1 mice. Attenuated oxidation of BH4 and inhibition of endothelial NO synthase uncoupling were explained by the increased expression of antioxidant proteins, manganese superoxide dismutase, and catalase. The protective effects of EPO observed in cerebral microvessels of hph1 mice were also observed in GTPCH-I siRNA-treated human brain microvascular endothelial cells exposed to EPO (1 U/mL or 10 U/mL; 3 days). Our results suggest that EPO might protect the neurovascular unit against oxidative stress by restoring bioavailability of BH4 and endothelial NO in the cerebral microvascular endothelium.
We demonstrate that treatment with erythropoietin (EPO) could protect cerebral microvasculature against the pathological consequences of endothelial nitric oxide (NO) synthase uncoupling. Our results suggest that EPO might protect the neurovascular unit against oxidative stress by restoring bioavailability of tetrahydrobiopterin (BH4) and endothelial nitric oxide.