Effects of ischemic post‐conditioning on neuronal VEGF regulation and microglial polarization in a rat model of focal cerebral ischemia. Issue 2 (16th May 2018)

• Record Type: Journal Article
• Authors: Esposito, Elga; Hayakawa, Kazuhide; Ahn, Bum Ju; Chan, Su Jing; Xing, Changhong; Liang, Anna C.; Kim, Kyu‐Won; Arai, Ken; Lo, Eng H.
• Is Part Of: Journal of neurochemistry. Volume 146:Issue 2(2018)
• Page Start: 160
• Page End: 172
• Publication Date: 2018-05-16
• Subjects: microglia -- neuroprotection -- neurovascular unit -- postconditioning -- stroke; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14337
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Ischemic postconditioning is increasingly being investigated as a therapeutic approach for cerebral ischemia. However, the majority of studies are focused on the acute protection of neurons per se . Whether and how postconditioning affects multiple cells in the recovering neurovascular unit remains to be fully elucidated. Here, we asked whether postconditioning may modulate help‐me signaling between injured neurons and reactive microglia. Rats were subjected to 100 min of focal cerebral ischemia, then randomized into a control versus postconditioning group. After 3 days of reperfusion, infarct volumes were significantly reduced in animals treated with postconditioning, along with better neurologic outcomes. Immunostaining revealed that ischemic postconditioning increased expression of vascular endothelial growth factor (VEGF) in neurons within peri‐infarct regions. Correspondingly, we confirmed that VEGFR2 was expressed on Iba1‐positive microglia/macrophages, and confocal microscopy showed that in postconditioned rats, these cells were polarized to a ramified morphology with higher expression of M2‐like markers. Treating rats with a VEGF receptor 2 kinase inhibitor negated these effects of postconditioning on microglia/macrophage polarization. In vitro, postconditoning after oxygen‐glucose deprivation up‐regulated VEGF release in primary neuron cultures, and adding VEGF to microglial cultures partly shifted their M2‐like markers. Altogether, our findings support the idea that after postconditioning, injured neurons may release VEGF as a 'help‐me' signal that promotes microglia/macrophage polarization into potentially beneficial phenotypes. Abstract : Our hypothesis is that ischemic postconditioning can promote neuroprotection by increasing the ability of the brain to "help itself" via cell‐cell interactions. We proposed that postconditioning may induce neurons to release VEGF as a "help‐me signal" that shifts microglia/macrophage into beneficial forms (M2‐like), and that this event can have a neuroprotective effect. Treatments with Flk‐1 inhibitor to block VEGF signaling annul the M2‐like microglia polarization and the neuroprotection after postconditioning.