Post-stroke Constraint-induced Movement Therapy Increases Functional Recovery, Angiogenesis, and Neurogenesis with Enhanced Expression of HIF-1α and VEGF

Background: Constraint-Induced Movement Therapy (CIMT) is one efficient approach to improve functional recovery after ischemic stroke. The underlying molecular mechanism remains unclear. In the current study, we investigated the effects of CIMT on angiogenesis and neurogenesis. To start linking our findings to molecular mediators, we further examined the expression of Hypoxia-Inducible Factor-1α (HIF-1α), Factor Inhibiting HIF-1 (FIH-1) and Vascular Endothelial Growth Factor (VEGF). Methods: Rats were randomly assigned into three groups: a Middle Cerebral Artery Occlusion group (MCAO), a therapeutic group (CIMT+MCAO), and a sham middle cerebral artery occlusion group (Sham). Seven days after surgery, a plaster cast was placed around the unimpaired upper limb of the rats in the CIMT+MCAO group for 14 days. CIMT was performed on a horizontal ladder. Neurobehavioral consequences were evaluated using the Open-Field Test (OFT) and the Foot-Fault Test (FFT). The number of new neurons, the length of vessels as well as the expression of HIF-1α, FIH-1, and VEGF were examined before and after 14 days of CIMT. Results: The CIMT+MCAO group showed a significant increase in the total length of microvessels and increased number of Bromodeoxyuridine+ (BrdU+)/NeuN+ double-labeled cells. These changes were correlated with an increase in HIF-1α and VEGF expressions and a decrease in FIH-1expression. FFT showed that the CIMT+MCAO group exhibited marked improvement in neurobehavioral outcome when compared to the MCAO group. Adverse effects on total activities or anxiety were not observed using open field analysis. Conclusion: CIMT-induced neuroprotection and functional recovery following cerebral ischemia were possibly mediated by an increase in endogenous HIF-1α and VEGF expression with subsequent neurogenesis and angiogenesis. Keywords: Stroke, constraint-induced movement therapy (CIMT), hypoxia-inducible factor (HIF), factor inhibiting HIF (FIH), vascular endothelial growth factor (VEGF), neurogenesis, angiogenesis.