Theta-burst transcranial magnetic stimulation promotes stroke recovery by vascular protection and neovascularization

Abstract

Rationale: The integrity and function of the blood-brain barrier (BBB) is compromised after stroke. The current study was performed to examine potential beneficial effects and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) on angiogenesis and vascular protection, function, and repair following stroke, which are largely unknown. Methods: Using a rat photothrombotic (PT) stroke model, continuous theta-burst rTMS was administered once daily to the infarcted hemisphere for 5 min, beginning 3 h after PT stroke. This treatment was applied for 6 days. BBB integrity, blood flow, vascular associated proteins, angiogenesis, integrity of neuronal morphology and structure, and behavioral outcome were measured and analyzed at 6 and/or 22 days after PT stroke. Results: We report that rTMS significantly mitigated BBB permeabilization and preserved important BBB components ZO-1, claudin-5, occludin, and caveolin-1 from PT-induced degradation. Damage to vascular structure, morphology, and perfusion was ameliorated by rTMS, resulting in improved local tissue oxygenation. This was accompanied with robust protection of critical vascular components and upregulation of regulatory factors. A complex cytokine response was induced by PT, particularly at the late phase. Application of rTMS modulated this response, ameliorating levels of cytokines related to peripheral immune cell infiltration. Further investigation revealed that rTMS promoted and sustained post-ischemic angiogenesis long-term and reduced apoptosis of newborn and existing vascular endothelial cells. Application of rTMS also inhibited PT-induced excessive astrocyte-vasculature interactions and stimulated an A1 to A2 shift in vessel-associated astrocytes. Mechanistic studies revealed that rTMS dramatically increased levels of PDGFRβ associated with A2 astrocytes and their adjacent vasculature. As well, A2 astrocytes displayed marked amplification of the angiogenesis-related factors VEGF and TGFβ. PT induced a rise in vessel-associated expression of HIF-1α that was starkly intensified by rTMS treatment. Finally, rTMS preserved neuronal morphology, synaptic structure integrity and behavioral outcome. Conclusions: These results indicate that rTMS can exert powerful protective and restorative effects on the peri-infarct microvasculature after PT stroke by, in part, promoting HIF-1α signaling and shifting vessel-associated astrocytic polarization to the A2 phenotype. This study provides further support for the potent protective effects of rTMS in the context of ischemic stroke, and these findings implicate vascular repair and protection as an important underlying phenomenon.

Reactive Astrocytes in Central Nervous System Injury: Subgroup and Potential Therapy

“…Epidermal growth factor-containing hydrogels can reportedly alter astrocyte behavior, i.e., they downregulate the expression of deleterious neurotoxicity-related genes ( Fbln5 and Rt1-S3 ) while upregulating that of potentially beneficial neuroprotective phenotype-associated genes ( Clcf1 , Tgm1 , and Ptgs2 ), thereby indirectly enhancing neuroprotection and neuroplasticity (Chan et al, 2019 ). RTMS, HSF1, and physical exercise also lead to the conversion of the neurotoxic phenotype into the neuroprotective phenotype, which promotes functional recovery after injury (Zong et al, 2020 ; Jiang et al, 2021 ; Li L. et al, 2021 ). Mitochondria may also play a role in A1 polarization.…”

Repetitive Transcranial Magnetic Stimulation Induces Quantified Functional and Structural Changes in Subcortical Stroke: A Combined Arterial Spin Labeling Perfusion and Diffusion Tensor Imaging Study

“…It can be inferred that after high-frequency rTMS treatment, neurogenesis and angiogenesis may occur in the injured pathway of the affected side, thus promoting the rehabilitation of motor function. The latest study of a rat photothrombotic stroke model showed that rTMS can significantly reduce the permeability of blood-brain barrier, improve vascular structure, morphology, and perfusion injury, promote and maintain angiogenesis after ischemia stroke for a long time ( Zong et al, 2020 ). Besides, by comparing the effects of real rTMS and sham rTMS, we found that the CBF decreased in the contralesional hemisphere and increased in the ipsilesional hemisphere.…”

Repetitive Transcranial Magnetic Stimulation for Neuropathic Pain and Neuropsychiatric Symptoms in Traumatic Brain Injury: A Systematic Review and Meta-Analysis

“…The results showed that rTMS could generate a significant and sustained improvement in postconcussive symptoms in mild TBI, which is in accordance with the findings of Baeken et al [ 66 ]. Moreover, rTMS has some superiority in that it can directly influence the brain, including regulating the prefrontal cortex, amygdala, and hippocampus [ 67 ], as well as expanding the cerebral blood vessels, thus improving microcirculation and cerebral blood flow [ 68 ]. As a result, the recovery of nerve function could be promoted, which could guide magnetoencephalogram activities to be normal and well organized [ 69 ].…”