Abstract 2393: Physical Activity Improves Long-Term Stroke Outcome via eNOS-Dependent Augmentation of Neo-Vascularization and Cerebral Blood Flow
Background: Physical activity upregulates endothelial nitric oxide synthase (eNOS), improves endothelial function, and protects from vascular disease. However, the long-term effects of voluntary running on neo-vascularization and functional recovery following mild brain ischemia are not known.
Methods and Results: 129/SV wild-type mice were exposed to 30 min middle cerebral artery occlusion and reperfusion (MCAo). Continuous voluntary running on wheels conferred long-term ~3– 4-fold upregulation of eNOS in the vasculature and of endothelial progenitor cells (EPCs) in the spleen, the blood and the bone marrow (Sca1/VEGFR2 FACS analysis; DiLDL/lectin labelling). Running upregulated eNOS expression in circulating EPC. This was associated with enhanced neo-vascularization in a disc model. Moreover, engraftment of transplanted TIE2/LacZ positive bone marrow-derived cells was increased in the ischemic brain. Four weeks after the insult, trained animals showed higher numbers of newly-generated cells in vascular sites (BrdU-labeling), increased density of perfused microvessels (Evans blue perfusion, tiled-field mapping), and sustained augmentation of cerebral blood flow within the ischemic striatum (14C-iodoantipyrine tissue equilibration). Moreover, running conferred tissue sparing and functional and cognitive improvement (Bederson-, wire-hanging-, Morris water maze tests) after 4 weeks. The protective effects of running on angiogenesis and outcome were completely abolished when animals were treated with a NOS inhibitor or the anti-angiogenic compound endostatin after brain ischemia, and in animals lacking eNOS expression.
Conclusion: Voluntary physical activity improves long-term stroke outcome by eNOS-dependent mechanisms related to improved angiogenesis and cerebral blood flow.