Enriched Environment Elicits Proangiogenic Mechanisms After Focal Cerebral Ischemia

Abstract

Brain has limited capacity for spontaneous recovery of lost function after stroke. Exposure to enriched environment (EE) can facilitate functional recovery, but mechanisms underlying this effect are poorly understood. Here, we used a middle cerebral artery occlusion (MCAO) model to investigate the impact of EE on angiogenesis in the post-ischemic brain in adult male Sprague Dawley rats, and examined whether blood-borne factors may contribute. Compared with standard cage (SC), exposure to EE was associated with greater improvement in neurological function, higher peri-infarct vascular density, and higher chronic post-ischemic cerebral blood flow assessed by laser speckle imaging. The effect persisted for at least 28 days. EE also enhanced the expression of hepatocyte growth factor in the peri-ischemic cortex when measured 15 days after MCAO. Interestingly, serum from rats exposed to EE after MCAO showed elevated levels of hepatocyte growth factor, and plasma or serum from rats exposed to EE after MCAO enhanced the survival and proliferation of cultured endothelial cells, in vitro, when compared with control plasma or serum from SC group after MCAO. Together, our data suggest that exposure to EE promotes angiogenesis in the ischemic brain that may in part be mediated by blood-borne factors.

MRI Evaluation of Axonal Remodeling After Combination Treatment With Xiaoshuan Enteric-Coated Capsule and Enriched Environment in Rats After Ischemic Stroke

“…XSEC individually decreased the infarct volume compared with that in vehicle group, and this effect was further boosted by the combined application of XSEC and EE. Notably, EE monotherapy did not produce beneficial effects in restoring brain infarct volume, which was in agreement with previous studies (Soderstrom et al, 2009;Xie et al, 2019). It should be also be noted that the combination treatment had an added beneficial effect as evidenced by significantly reduced atrophy of the ipsilateral hemisphere following an ischemic stroke, whereas the monotherapies showed no effect.…”

Effectiveness of immersive VR-based rehabilitation on upper extremity recovery in subacute stroke: a randomized controlled trial

“…The imVR system used here incorporates a wide field of view, high resolution, head-mounted display (HMD), and auditory and tactile/force feedback [64] to provide an enriched environment (EE), exposing subjects to enhanced motor, sensory, cognitive, and social stimuli relative to a standard condition [65]. Animal studies suggest that exposure to EE promotes angiogenesis in ischemic brains [66], induces behavioral and neurobiological changes [67, 68], synaptic plasticity changes [69], and enhances sensorimotor function [65]. In addition, a clinical trial demonstrated that exposure to EE was associated with increased activity levels, improved function, mood and quality of life of stroke survivors in a cost-saving manner [70].…”

The role of enriched environment in neural development and repair

“…The mechanism underlying angiogenesis may be mediated by hepatocyte growth factor, a blood-derived factor, which was elevated by EE in cortex and serum after middle cerebral artery occlusion (MCAO). The statement stems from the finding that survival and proliferation of endothelial cells were significantly improved when co-cultured with serum and plasma derived from EE after ischemia (Xie et al, 2019 ). In addition, magnetic resonance angiography showed selective amplification of basilar, internal carotid, and middle cerebral artery signals after MCAO via a three-stage EE paradigm designed according to different stages of cerebral ischemia, which was regulated partially by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase-3 (GSK-3)/β-catenin and the axon guidance molecules (Zhan et al, 2020 ).…”