Exercise Promotes Collateral Artery Growth Mediated by Monocytic Nitric Oxide

What exercise does your doctor recommend for the best response?
http://atvb.ahajournals.org/content/35/8/1862.abstract?etoc

1. Stephan H. Schirmer,
2. Dominic N. Millenaar,
3. Christian Werner,
4. Lisa Schuh,
5. Achim Degen,
6. Stephanie I. Bettink,
7. Peter Lipp,
8. Nico van Rooijen,
9. Tim Meyer,
10. Michael Böhm,
11. Ulrich Laufs

+ Author Affiliations

1. From the Klinik für Innere Medizin III (S.H.S., D.N.M., C.W., L.S., A.D., S.I.B., M.B., U.L.) and Institut für Molekulare Zellbiologie (P.L.), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, VUMC, Amsterdam, The Netherlands (N.R.); and Institut für Sport- und Präventivmedizin, Universität des Saarlandes, Saarbrücken, Germany (T.M.).

1. Correspondence to Stephan H. Schirmer, MD, PhD, Klinik für Innere Medizin III, Kardiologie, Angiology und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße, Geb. 40, 66421 Homburg/Saar, Germany. E-mail Stephan.Schirmer@uks.eu

Abstract

Objective—Collateral artery growth (arteriogenesis) is an important adaptive response to hampered arterial perfusion. It is unknown whether preventive physical exercise before limb ischemia can improve arteriogenesis and modulate mononuclear cell function. This study aimed at investigating the effects of endurance exercise before arterial occlusion on MNC function and collateral artery growth.

Approach and Results—After 3 weeks of voluntary treadmill exercise, ligation of the right femoral artery was performed in mice. Hindlimb perfusion immediately after surgery did not differ from sedentary mice. However, previous exercise improved perfusion restoration ≤7 days after femoral artery ligation, also when exercise was stopped at ligation. This was accompanied by an accumulation of peri-collateral macrophages and increased expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) in hindlimb collateral and in MNC of blood and spleen. Systemic monocyte and macrophage depletion by liposomal clodronate but not splenectomy attenuated exercise-induced perfusion restoration, collateral artery growth, peri-collateral macrophage accumulation, and upregulation of iNOS. iNOS-deficient mice did not show exercise-induced perfusion restoration. Transplantation of bone marrow–derived MNC from iNOS-deficient mice into wild-type animals inhibited exercise-induced collateral artery growth. In contrast to sedentary controls, thrice weekly aerobic exercise training for 6 months in humans increased peripheral blood MNC iNOS expression.

Conclusions—Circulating mononuclear cell–derived inducible nitric oxide is an important mediator of exercise-induced collateral artery growth.