Essential role of endothelial nitric oxide synthase in vascular effects of erythropoietin.
Erythropoietin (EPO) fosters tissue oxygenation by stimulating erythropoiesis. More recently, EPO has been recognized as a tissue-protective cytokine. In this study, we tested the hypothesis that endothelial NO synthase (eNOS) plays a key role in the vascular protective effect of EPO. A murine model of wire-induced injury of carotid artery was used to examine the effect of EPO on endothelial repair and arterial wall architecture. Recombinant human EPO (1000 U/kg, SC, biweekly) was administered for 2 weeks in wild-type and eNOS-deficient mice after which reactivity of isolated carotid arteries was studied in vitro, and the vasculature was histologically assessed. Injured arteries exhibited impairment of endothelium-dependent relaxations to acetylcholine (P<0.05). This was associated with increased medial cross-sectional area (P<0.05). EPO upregulated expression of phosphorylated Ser1177-eNOS and normalized the vasodilator response to acetylcholine (P<0.05). Furthermore, EPO prevented the injury-induced increase in medial cross-sectional area (P<0.05). The vascular protective effects of EPO were abolished in eNOS-deficient mice. Most notably, EPO significantly increased systolic blood pressure and enhanced medial thickening of injured carotid arteries in eNOS-deficient mice (P<0.05). Our results demonstrate that EPO prevents aberrant remodeling of the injured carotid artery. The protective effects of EPO are critically dependent on activation of eNOS.
d'Uscio
Livius V
LV
Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Smith
Leslie A
LA
Santhanam
Anantha V
AV
Richardson
Darcy
D
Nath
Karl A
KA
Katusic
Zvonimir S
ZS
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D017536:Carotid Artery, Common / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D019610:Cytoprotection; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000378:metabolism*; D011994:Recombinant Proteins; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects*
D011994:Recombinant Proteins; D014665:Vasodilator Agents; D004921:Erythropoietin; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine