Ablation of matrix metalloproteinase-9 gene decreases cerebrovascular permeability and fibrinogen deposition post traumatic brain injury in mice.
Traumatic brain injury (TBI) is accompanied with enhanced matrix metalloproteinase-9 (MMP-9) activity and elevated levels of plasma fibrinogen (Fg), which is a known inflammatory agent. Activation of MMP-9 and increase in blood content of Fg (i.e. hyperfibrinogenemia, HFg) both contribute to cerebrovascular disorders leading to blood brain barrier disruption. It is well-known that activation of MMP-9 contributes to vascular permeability. It has been shown that at an elevated level (i.e. HFg) Fg disrupts blood brain barrier. However, mechanisms of their actions during TBI are not known. Mild TBI was induced in wild type (WT, C57BL/6 J) and MMP-9 gene knockout (Mmp9(-/-)) homozygous, mice. Pial venular permeability to fluorescein isothiocyanate-conjugated bovine serum albumin in pericontusional area was observed 14 days after injury. Mice memory was tested with a novel object recognition test. Increased expression of Fg endothelial receptor intercellular adhesion protein-1 and formation of caveolae were associated with enhanced activity of MMP-9 causing an increase in pial venular permeability. As a result, an enhanced deposition of Fg and cellular prion protein (PrP(C)) were found in pericontusional area. These changes were attenuated in Mmp9(-/-) mice and were associated with lesser loss of short-term memory in these mice than in WT mice. Our data suggest that mild TBI-induced increased cerebrovascular permeability enhances deposition of Fg-PrP(C) and loss of memory, which is ameliorated in the absence of MMP-9 activity. Thus, targeting MMP-9 activity and blood level of Fg can be a possible therapeutic remedy to diminish vasculo-neuronal damage after TBI.
Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY, USA.
Nino
N
Muradashvili
Richard L
RL
Benton
Kathryn E
KE
Saatman
Suresh C
SC
Tyagi
David
D
Lominadze
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001930:Brain Injuries / Q000235:genetics* / Q000378:metabolism* / Q000523:psychology; D002196:Capillaries / Q000473:pathology; D002540:Cerebral Cortex / Q000293:injuries; D002550:Cerebral Veins / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000235:genetics*; D003288:Contusions / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D005340:Fibrinogen / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics / Q000523:psychology; D008570:Memory, Short-Term; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010539:Permeability; D018621:PrPC Proteins / Q000378:metabolism
D018621:PrPC Proteins; D018799:Intercellular Adhesion Molecule-1; D005340:Fibrinogen; D020780:Matrix Metalloproteinase 9