Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 19, Pages 7505-7510Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1121146109
Keywords
reactive glia; vascular repair; brain remodeling
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Funding
- Deane Foundation
- American Heart Association
- National Institutes of Health
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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 end-products 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.
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