Exercise Promotes Collateral Artery Growth Mediated by Monocytic Nitric Oxide

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 iNOSdeficient 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.

The “Intermediate” CD14++CD16+ monocyte subset increases in severe peripheral artery disease in humans

“…Replenishing these potentially reparative CD14 + CD16 ++ monocytes might provide a novel therapeutic option. Evidence that mononuclear cell transfer can mediate exercise-induced collateral artery growth in mice illustrates monocyte transfer as an amenable therapeutic approach21.…”

The genetics of exceptional longevity identifies new druggable targets for vascular protection and repair

“…Together with neuronal NOS (nNOS), eNOS is constitutively expressed. On the other hand, a third form of NOS, inducible NOS (iNOS), is produced in response to insults in monocytes/macrophages, but also in MNCs with angiogenic activity, with recent evidences pointing to a potential role of iNOS in the control of angiogenesis (27)(28)(29).…”

Redox Control of Vascular Function

“…89,90 Additional research has shown that excess NO, often due to inducible NOS (iNOS) leads to loss of endothelial integrity in diseases like atherosclerosis, 91 despite the fact that exercise was shown to promote healthy arteriogenesis in an iNOS-dependent manner. 92 …”