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Erythropoietin-induced hypertension and vascular injury in mice overexpressing human endothelin-1: exercise attenuated hypertension, oxidative stress, inflammation and immune response

Barhoumi, Tlilia,d; Briet, Mariea,b,e; Kasal, Daniel A.a,c; Fraulob-Aquino, Julio Cesara; Idris-Khodja, Nourredinea; Laurant, Pascald; Paradis, Pierrea; Schiffrin, Ernesto L.a,b

doi: 10.1097/HJH.0000000000000101
ORIGINAL PAPERS: Pathophysiological aspects

Objective: Erythropoietin used to correct anaemia in chronic kidney disease (CKD) has been shown to increase blood pressure (BP) in CKD patients and experimental animals. Endothelin (ET)-1 expression is increased in CKD animals and patients, and enhanced by erythropoietin. Erythropoietin-induced BP rise was blunted by ETA receptor blockers. This study was designed to determine whether preexisting endothelin (ET)-1 overexpression is required for erythropoietin to cause adverse vascular effects and whether this could be prevented by exercise training.

Methods: Eight to 10-week old male wild-type mice and mice with endothelial-specific ET-1 overexpression (eET-1) were treated or not with EPO (100 IU/kg, SC, 3 times/week). eET-1 was subjected or not to swimming exercise training (1 h/day, 6 days/week) for 8 weeks. SBP, mesenteric artery endothelial function and remodelling, NADPH oxidase activity, reactive oxygen species (ROS) generation, vascular cell adhesion protein (VCAM)-1, monocyte/macrophage infiltration, T regulatory cells (Tregs) and tissue ET-1 and plasma endothelin were determined.

Results: Erythropoietin increased SBP by 24 mmHg (P < 0.05) and decreased by 25% vasodilatory responses to acetylcholine (P < 0.01) in eET-1 mice. Erythropoietin enhanced ET-1 induced increase in resistance artery media/lumen ratio (31%, P < 0.05), aortic NADPH oxidase activity (50%, P < 0.05), ROS generation (93%, P < 0.001), VCAM-1 (80%, P < 0.01) and monocyte/macrophage infiltration (159%, P < 0.001), and raised plasma and aortic ET-1 levels (≥130%, P < 0.05). EPO had no effect in wild-type mice. Exercise training prevented all of the above (P < 0.05).

Conclusion: Erythropoietin-induced adverse vascular effects are dependent on preexisting elevated ET-1 expression. Exercise training prevented erythropoietin-induced adverse vascular effects in part by inhibiting ET-1 overexpression-induced oxidative stress, inflammation and immune activation.

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aLady Davis Institute for Medical Research

bDepartment of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada

cState University of Rio de Janeiro, Rio de Janeiro, Brazil

dUniversité d’Avignon et des Pays de Vaucluse-Avignon, Avignon

eDepartment of Pharmacology and Institut National de la Santé et de la Recherche Médicale U970-PARCC, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France

Correspondence to Ernesto L. Schiffrin, CM, MD, PhD, FRSC, FRCPC, Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, #B-127, 3755 Cote Ste-Catherine Road, Montreal, QC H3T 1E2, Canada. Tel: +1 514 340 7538; fax: +1 514 340 7539; e-mail:

Abbreviations: ACh, acetylcholine; BP, blood pressure; CKD, chronic kidney disease; DAPI, 4’,6-diamidino-2-phenylindole; DHE, dihydroethidium; eET-1, mice with endothelium-specific endothelin-1 overexpression; EPO, erythropoietin; ET, endothelin; ETAR, endothelin type A receptor; FOXP3, forkhead box P3; L-NAME, N ω-nitro-L-arginine methyl ester; PBST, phosphate buffered saline containing 0.1% Tween-20; RAB, reactive oxygen species assay buffer; ROS, reactive oxygen species; Treg, T regulatory lymphocytes; VCAM-1, vascular cell adhesion protein 1

Received 13 May, 2012

Accepted 4 December, 2013

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