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Exercise training restores the endothelial progenitor cells number and function in hypertension: implications for angiogenesis

Fernandes, Tiago; Nakamuta, Juliana S.; Magalhães, Flávio C.; Roque, Fernanda R.; Lavini-Ramos, Carolina; Schettert, Isolmar T.; Coelho, Verônica; Krieger, José E.; Oliveira, Edilamar M.

doi: 10.1097/HJH.0b013e3283588d46

Objectives: Aerobic exercise training has been established as an important nonpharmacological treatment for hypertension. We investigated whether the number and function of endothelial progenitor cells (EPCs) are restored after exercise training, potentially contributing to neovascularization in hypertension.

Methods: Twelve-week-old male spontaneously hypertensive rats (SHRs, n = 14) and Wistar–Kyoto (WKY, n = 14) rats were assigned to four groups: SHR; trained SHR (SHR-T); WKY; and trained WKY. Exercise training consisted of 10 weeks of swimming. EPC number and function, as well as the vascular endothelial growth factor (VEGF), nitrotyrosine and nitrite concentration in peripheral blood were quantified by fluorescence-activated cell sorter analysis (CD34+/Flk1+ cells), colony-forming unit assay, ELISA and nitric oxide (NO) analyzer, respectively. Soleus capillary/fiber ratio and protein expression of VEGF and endothelial NO synthase (eNOS) by western blot were assessed.

Results: Exercise training was effective in reducing blood pressure in SHR-T accompanied by resting bradycardia, an increase in exercise tolerance, peak oxygen uptake (VO2) and citrate synthase activity. In response to hypertension, the amount of peripheral blood-EPC and number of colonies were decreased in comparison with control levels. In contrast, exercise training normalized the EPC levels and function in SHR-T accompanied by an increase in VEGF and NO levels. In addition, oxidative stress levels were normalized in SHR-T. Similar results were found in the number and function of bone marrow EPC. Exercise training repaired the peripheral capillary rarefaction in hypertension by a signaling pathway VEGF/eNOS-dependent in SHR-T. Moreover, improvement in EPC was significantly related to angiogenesis.

Conclusion: Our data show that exercise training repairs the impairment of EPC in hypertension, which could be associated with peripheral revascularization, suggesting a mechanism for its potential therapeutic application in vascular diseases.

aLaboratory of Biochemistry and Molecular Biology of the Exercise, School of Physical Education and Sport

bLaboratory of Genetics and Molecular Cardiology

cLaboratory of Immunology, Heart Institute, Medical School, University of Sao Paulo, Sao Paulo, Brazil

Correspondence to Edilamar M. Oliveira, Laboratory of Biochemistry and Molecular Biology of the Exercise, School of Physical Education and Sport, University of Sao Paulo, Av. Professor Mello Moraes, 65 Cidade Universitária, São Paulo, SP 05508–900, Brazil. Tel: +55 11 3091 2118; fax: +55 11 3813 5921; e-mail:

Abbreviations: CVD, cardiovascular disease; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cell; FACS, fluorescence-activated cell sorter; HR, heart rate; iNOS, inducible nitric oxide synthase; MNC, mononuclear cell; NO, nitric oxide; ROS, reactive oxygen species; SA-ß-gal, senescence-associated β-galactosidase; SHR, spontaneously hypertensive rat; SHR-T, swimming-trained SHR; VEGF, vascular endothelial growth factor; VO2, oxygen uptake; WKY, Wistar–Kyoto; WKY-T, swimming-trained WKY

Received 19 January, 2012

Revised 24 June, 2012

Accepted 25 July, 2012

Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.