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Effects of ischemic post‐conditioning on neuronal VEGF regulation and microglial polarization in a rat model of focal cerebral ischemia
Author(s) -
Esposito Elga,
Hayakawa Kazuhide,
Ahn Bum Ju,
Chan Su Jing,
Xing Changhong,
Liang Anna C.,
Kim KyuWon,
Arai Ken,
Lo Eng H.
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14337
Subject(s) - microglia , ischemia , immunostaining , neuroinflammation , macrophage polarization , vascular endothelial growth factor , medicine , pathology , neuroscience , inflammation , pharmacology , microbiology and biotechnology , macrophage , biology , immunology , cancer research , immunohistochemistry , in vitro , vegf receptors , biochemistry
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 VEGFR 2 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.