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.
| Original language | English |
|---|---|
| Pages (from-to) | 919-932 |
| Number of pages | 14 |
| Journal | Journal of Cerebral Blood Flow and Metabolism |
| Volume | 32 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2012 May 1 |
| Externally published | Yes |
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Keywords
- hemorrhage
- ischemic stroke
- metalloproteinases
- microglia
- microvascular dysfunction
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
- Cardiology and Cardiovascular Medicine
Cite this
Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. / Del Zoppo, Gregory J.; Frankowski, Harald; Gu, Yu Huan; Osada, Takashi; Kanazawa, Masato; Milner, Richard; Wang, Xiaoyun; Hosomi, Naohisa; Mabuchi, Takuma; Koziol, James A.
In: Journal of Cerebral Blood Flow and Metabolism, Vol. 32, No. 5, 01.05.2012, p. 919-932.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation
AU - Del Zoppo, Gregory J.
AU - Frankowski, Harald
AU - Gu, Yu Huan
AU - Osada, Takashi
AU - Kanazawa, Masato
AU - Milner, Richard
AU - Wang, Xiaoyun
AU - Hosomi, Naohisa
AU - Mabuchi, Takuma
AU - Koziol, James A.
PY - 2012/5/1
Y1 - 2012/5/1
N2 - 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.
AB - 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.
KW - hemorrhage
KW - ischemic stroke
KW - metalloproteinases
KW - microglia
KW - microvascular dysfunction
UR - http://www.scopus.com/inward/record.url?scp=84862777406&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862777406&partnerID=8YFLogxK
U2 - 10.1038/jcbfm.2012.11
DO - 10.1038/jcbfm.2012.11
M3 - Article
VL - 32
SP - 919
EP - 932
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 5
ER -