TY - JOUR
T1 - In vivo stimulatory effect of erythropoietin on endothelial nitric oxide synthase in cerebral arteries
AU - Santhanam, Anantha Vijay R.
AU - Smith, Leslie A.
AU - Nath, Karl A.
AU - Katusic, Zvonimir S.
PY - 2006
Y1 - 2006
N2 - The discovery of tissue protective effects of erythropoietin has stimulated significant interest in erythropoietin (Epo) as a novel therapeutic approach to vascular protection. The present study was designed to determine the cerebral vascular effects of recombinant Epo in vivo. Recombinant adenoviral vectors (109 plaque-forming units/animal) encoding genes for human erythropoietin (AdEpo) and β-galactosidase (AdLacZ) were injected into the cisterna magna of rabbits. After 48 h, basilar arteries were harvested for analysis of vasomotor function, Western blotting, and measurement of cGMP levels. Gene transfer of AdEpo increased the expressions of recombinant Epo and its receptor in the basilar arteries. Arteries exposed to recombinant Epo demonstrated attenuation of contractile responses to histamine (10-9 to 10-5 mol/l) (P < 0.05, n = 5). Endothelium-dependent relaxations to acetylcholine (10-9 to 10-5 mol/l) were significantly augmented (P < 0.05, n = 5), whereas endothelium-independent relaxations to a nitric oxide (NO) donor 2-(N,N-diethylamino)diazenolate-2-oxide sodium salt remained unchanged in AdEpo-transduced basilar arteries. Transduction with AdEpo increased the protein expression of endothelial NO synthase (eNOS) and phosphorylated the S1177 form of the enzyme. Basal levels of cGMP were significantly elevated in arteries transduced with AdEpo consistent with increased NO production. Our studies suggest that in cerebral circulation, Epo enhances endothelium-dependent vasodilatation mediated by NO. This effect could play an important role in the vascular protective effect of Epo.
AB - The discovery of tissue protective effects of erythropoietin has stimulated significant interest in erythropoietin (Epo) as a novel therapeutic approach to vascular protection. The present study was designed to determine the cerebral vascular effects of recombinant Epo in vivo. Recombinant adenoviral vectors (109 plaque-forming units/animal) encoding genes for human erythropoietin (AdEpo) and β-galactosidase (AdLacZ) were injected into the cisterna magna of rabbits. After 48 h, basilar arteries were harvested for analysis of vasomotor function, Western blotting, and measurement of cGMP levels. Gene transfer of AdEpo increased the expressions of recombinant Epo and its receptor in the basilar arteries. Arteries exposed to recombinant Epo demonstrated attenuation of contractile responses to histamine (10-9 to 10-5 mol/l) (P < 0.05, n = 5). Endothelium-dependent relaxations to acetylcholine (10-9 to 10-5 mol/l) were significantly augmented (P < 0.05, n = 5), whereas endothelium-independent relaxations to a nitric oxide (NO) donor 2-(N,N-diethylamino)diazenolate-2-oxide sodium salt remained unchanged in AdEpo-transduced basilar arteries. Transduction with AdEpo increased the protein expression of endothelial NO synthase (eNOS) and phosphorylated the S1177 form of the enzyme. Basal levels of cGMP were significantly elevated in arteries transduced with AdEpo consistent with increased NO production. Our studies suggest that in cerebral circulation, Epo enhances endothelium-dependent vasodilatation mediated by NO. This effect could play an important role in the vascular protective effect of Epo.
KW - Gene transfer
KW - Rabbit
KW - Recombinant adenoviral vectors
KW - Vasodilatation
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U2 - 10.1152/ajpheart.00045.2006
DO - 10.1152/ajpheart.00045.2006
M3 - Article
C2 - 16565320
AN - SCOPUS:33746785520
SN - 0363-6135
VL - 291
SP - H781-H786
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 2
ER -