Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement

TY - JOUR

T1 - Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement

AU - Bauer, Alexander T

AU - Bürgers, Heinrich F

AU - Rabie, Tamer

AU - Marti, Hugo H

PY - 2010/4

Y1 - 2010/4

N2 - Blood-brain barrier (BBB) disruption, resulting from loss of tight junctions (TJ) and activation of matrix metalloproteinases (MMPs), is associated with edema formation in ischemic stroke. Cerebral edema develops in a phasic manner and consists of both vasogenic and cytotoxic components. Although it is contingent on several independent mechanisms, involving hypoxic and inflammatory responses, the single effect of prolonged hypoxia on BBB integrity in vivo was not addressed so far. Exposing mice to normobaric hypoxia (8% oxygen for 48 h) led to a significant increase in vascular permeability associated with diminished expression of the TJ protein occludin. Immunofluorescence studies revealed that hypoxia resulted in disrupted continuity of occludin and zonula occludens-1 (Zo-1) staining with significant gap formation. Hypoxia increased gelatinolytic activity specifically in vascular structures and gel zymography identified MMP-9 as enzymatic source. Treatment with an MMP inhibitor reduced vascular leakage and attenuated disorganization of TJ. Inhibition of vascular endothelial growth factor (VEGF) attenuated vascular leakage and MMP-9 activation induced by hypoxia. In conclusion, our data suggest that hypoxia-induced edema formation is mediated by MMP-9-dependent TJ rearrangement by a mechanism involving VEGF. Therefore, inhibition of MMP-9 might provide the basis for therapeutic strategies to treat brain edema.

AB - Blood-brain barrier (BBB) disruption, resulting from loss of tight junctions (TJ) and activation of matrix metalloproteinases (MMPs), is associated with edema formation in ischemic stroke. Cerebral edema develops in a phasic manner and consists of both vasogenic and cytotoxic components. Although it is contingent on several independent mechanisms, involving hypoxic and inflammatory responses, the single effect of prolonged hypoxia on BBB integrity in vivo was not addressed so far. Exposing mice to normobaric hypoxia (8% oxygen for 48 h) led to a significant increase in vascular permeability associated with diminished expression of the TJ protein occludin. Immunofluorescence studies revealed that hypoxia resulted in disrupted continuity of occludin and zonula occludens-1 (Zo-1) staining with significant gap formation. Hypoxia increased gelatinolytic activity specifically in vascular structures and gel zymography identified MMP-9 as enzymatic source. Treatment with an MMP inhibitor reduced vascular leakage and attenuated disorganization of TJ. Inhibition of vascular endothelial growth factor (VEGF) attenuated vascular leakage and MMP-9 activation induced by hypoxia. In conclusion, our data suggest that hypoxia-induced edema formation is mediated by MMP-9-dependent TJ rearrangement by a mechanism involving VEGF. Therefore, inhibition of MMP-9 might provide the basis for therapeutic strategies to treat brain edema.

KW - Animals

KW - Blood-Brain Barrier/metabolism

KW - Brain Edema/etiology

KW - Capillary Permeability/physiology

KW - Cerebrovascular Circulation/physiology

KW - Enzyme Activation

KW - Hypoxia/metabolism

KW - Male

KW - Matrix Metalloproteinase 9/metabolism

KW - Membrane Proteins/genetics

KW - Mice

KW - Occludin

KW - Phosphoproteins/genetics

KW - Stroke/complications

KW - Tight Junctions/metabolism

KW - Vascular Endothelial Growth Factor A/antagonists & inhibitors

KW - Zonula Occludens-1 Protein

U2 - 10.1038/jcbfm.2009.248

DO - 10.1038/jcbfm.2009.248

M3 - SCORING: Journal article

C2 - 19997118

VL - 30

SP - 837

EP - 848

JO - J CEREBR BLOOD F MET

JF - J CEREBR BLOOD F MET

SN - 0271-678X

IS - 4

ER -