Published Online
on March 19, 2007

A more recent version of this article appeared on May 1, 2007

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Submitted on December 7, 2006
Revised on December 31, 2006

Essential Role of Endothelial Nitric Oxide Synthase in Vascular Effects of Erythropoietin

Livius V. d’Uscio; Leslie A. Smith; Anantha V. Santhanam; Darcy Richardson; Karl A. Nath; and Zvonimir S. Katusic^*

From the Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics (L.V.d.U., L.A.S., A.V.S., D.R., Z.S.K.) and the Division of Nephrology and Hypertension, Department of Internal Medicine (K.A.N.), Mayo Clinic College of Medicine, Rochester, Minn.

^* To whom correspondence should be addressed. E-mail: katusic.zvonimir{at}mayo.edu.

Abstract--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.

Key words: nitric oxide synthase • endothelium • vasculature • erythropoietin • mice

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