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

J Hypertens. 2014 Apr;32(4):784-94. doi: 10.1097/HJH.0000000000000101.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure
  • Endothelin-1 / blood*
  • Erythropoietin / blood*
  • Hematocrit
  • Humans
  • Hypertension / physiopathology*
  • Immune System
  • Inflammation
  • Male
  • Mice
  • Mice, Transgenic
  • NADPH Oxidases / metabolism
  • Oxidative Stress*
  • Physical Conditioning, Animal
  • Reactive Oxygen Species
  • Swimming
  • Systole


  • Endothelin-1
  • Reactive Oxygen Species
  • Erythropoietin
  • NADPH Oxidases