Exercise Therapy Augments the Ischemia-Induced Proangiogenic State and Results in Sustained Improvement after Stroke

Yuewen Ma,Lin Qiang,Man He

doi:10.3390/ijms14048570

Abstract

The induction of angiogenesis will stimulate endogenous recovery mechanisms, which are involved in the long-term repair and restoration process of the brain after an ischemic event. Here, we tested whether exercise influences the pro-angiogenic factors and outcomes after cerebral infarction in rats. Wistar rats were exposed to two hours of middle-cerebral artery occlusion and reperfusion. Different durations of treadmill training were performed on the rats. The expression of matrix metalloproteinase 2 (MMP2) and vascular endothelial growth factor (VEGF)-related genes and proteins were higher over time post-ischemia, and exercise enhanced their expression. Sixteen days post-ischemia, the regional cerebral blood flow in the ischemic striatum was significantly increased in the running group over the sedentary. Although no difference was seen in infarct size between the running and sedentary groups, running evidently improved the neurobehavioral score. The effects of running on MMP2 expression, regional cerebral blood flow and outcome were abolished when animals were treated with bevacizumab (BEV), a VEGF-targeting antibody. Exercise therapy improves long-term stroke outcome by MMP2-VEGF-dependent mechanisms related to improved cerebral blood flow.

Highlights

Exercise therapy is a well-known component of stroke rehabilitation programs [1,2,3]
We demonstrated the role of vascular endothelial growth factor (VEGF) signaling in exercise-induced matrix metalloproteinase 2 (MMP2) upregulation and increased absolute regional cerebral blood flow (rCBF), a role that appeared to mediate the protective effects of regular physical activity
As it was revealed that when animals were co-treated with BEV, the running effects on MMP2 upregulation, rCBF and outcome were apparently weakened, a finding indicated that increased VEGF bioavailability may stimulate

Summary

Introduction

Exercise therapy is a well-known component of stroke rehabilitation programs [1,2,3]. The newborn neuroblasts migrate along peri-vascular routes [4], and promotion of angiogenesis stimulates endogenous recovery mechanisms [5,6,7,8]. Exercise preconditioning enhances cerebrovascular integrity [9] and improves angiogenesis and cerebral blood flow [10] in ischemic rats. Clarifying the molecular mechanisms by which exercise exerts its functions in neurovascular remodeling may offer a potential breakthrough for the development of new methods that improve long-term outcome after stroke. It has become clear that VEGF is important in the hypoxic initiation of endothelial cell proliferation and migration that are required for angiogenesis to occur [17]. To accommodate the migration of the proliferating cells, a finely regulated degradation of the basement membrane and surrounding extracellular matrix (ECM) must occur

Results

Discussion

Conclusion