Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery

Kazuhide Hayakawa, Loc Duyen D. Pham, Zvonimir S. Katusic, Ken Arai, Eng H. Lo

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

Abstract

Crosstalk between the brain and systemic responses in blood is increasingly suspected of playing critical roles in stroke. However, how this communication takes place remains to be fully understood. Here, we show that reactive astrocytes can release a damage- associated molecular-pattern molecule called high-mobilitygroup- box-1 (HMGB1) that promotes endothelial progenitor cell (EPC)-mediated neurovascular remodeling during stroke recovery. Conditioned media from reactive astrocytes increase EPC proliferation in vitro. siRNA suppression of HMGB1 in astrocytes or blockade of the HMGB1 receptor for advanced glycation endproducts in EPCs prevents this effect. In a mouse model of focal cerebral ischemia, reactive astrocytes in the peri-infarct cortex upregulate HMGB1 at 14 d poststroke, along with an accumulation of endogenous EPCs. In vivo siRNA suppression of HMGB1 blocks this EPC response, reduces peri-infact angiogenesis, and worsens neurological deficits. Taken together, these molecular and in vivo findings support a previously undescribed mechanism of crosstalk between reactive astrocytes and EPCs wherein HMGB1 promotes neurovascular remodeling and functional recovery after stroke and brain injury.

Original languageEnglish (US)
Pages (from-to)7505-7510
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number19
DOIs
StatePublished - May 8 2012

Keywords

  • Brain remodeling
  • Reactive glia
  • Vascular repair

ASJC Scopus subject areas

  • General

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