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J Cereb Blood Flow Metab. 2012 May;32(5):919-32. doi: 10.1038/jcbfm.2012.11. Epub 2012 Feb 22.

Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation.

Author information

1
Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA. grgdlzop@u.washington.edu

Abstract

Hemorrhage and edema accompany evolving brain tissue injury after ischemic stroke. In patients, these events have been associated with metalloproteinase (MMP)-9 in plasma. Both the causes and cellular sources of MMP-9 generation in this setting have not been defined. MMP-2 and MMP-9 in nonhuman primate tissue in regions of plasma leakage, and primary murine microglia and astrocytes, were assayed by immunocytochemistry, zymography, and real-time RT-PCR. Ischemia-related hemorrhage was associated with microglial activation in vivo, and with the leakage of plasma fibronectin and vitronectin into the surrounding tissue. In strict serum-depleted primary cultures, by zymography, pro-MMP-9 was generated by primary murine microglia when exposed to vitronectin and fibronectin. Protease secretion was enhanced by experimental ischemia (oxygen-glucose deprivation, OGD). Primary astrocytes, on each matrix, generated only pro-MMP-2, which decreased during OGD. Microglia-astrocyte contact enhanced pro-MMP-9 generation in a cell density-dependent manner under normoxia and OGD. Compatible with observations in a high quality model of focal cerebral ischemia, microglia, but not astrocytes, respond to vitronectin and fibronectin, found when plasma extravasates into the injured region. Astrocytes alone do not generate pro-MMP-9. These events explain the appearance of MMP-9 antigen in association with ischemia-induced cerebral hemorrhage and edema.

PMID:
22354151
PMCID:
PMC3345906
DOI:
10.1038/jcbfm.2012.11
[Indexed for MEDLINE]
Free PMC Article

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