Ablation of matrix metalloproteinase-9 gene decreases cerebrovascular permeability and fibrinogen deposition post traumatic brain injury in mice

Abstract

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/6J) and MMP-9 gene knockout (Mmp9−/−) homozygous, mice. Pial venular permeability to fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) 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 (PrPC) 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-PrPC 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.

Cerebrovascular disorders caused by hyperfibrinogenaemia

“…Brain pial microcirculation was prepared for observations according to the method described previously (Muradashvili et al . a , b , c , ). Briefly, a mouse was placed on a stereotaxic apparatus (World Precision Instruments, Sarasota, FL, USA).…”

“…), were used in combination to define the formation of caveoli in the vessels of brain samples as described previously (Muradashvili et al . a , c ; ). Fluorescence intensity was measured in AOI along the vessel wall and data were normalized by the length of the respective vascular segment.…”

“…Our previous study also points to the role of PrP C in memory impairment (Muradashvili et al . ). Therefore, formation of Fg–Aβ and/or Fg–PrP C complexes may indicate a mechanism for memory reduction seen in diseases associated with cerebrovascular impairment.…”

A Precision Medicine Approach to Cerebral Edema and Intracranial Hypertension after Severe Traumatic Brain Injury: Quo Vadis?

“…Preclinical TBI models with MMP-9 inhibition (including SB-3CT, a highly selective MMP-2 and MMP-9 inhibitor) have shown improvement in BBB integrity (from reduced tight junction protein degradation and decreased vascular permeability) attenuated microglial activation, and reduced lesion volume; the effect on outcome has been controversial [145, 185-190]. In part, this may be due to the involvement of MMP-9 in neurovascular modeling and repair [124, 191]; timing of MMP-9 inhibition may thus be critical in terms of impact on edema and outcome.…”

Regulation and involvement of matrix metalloproteinases in vascular diseases

“…Furthermore, our group has demonstrated that hyperhomocysteinemia enhanced cerebrovascular permeability through activation of MMP-9 and increased the formation of fibrinogen-β-amyloid complex within the brain (42). Additionally, increased cerebrovascular permeability and memory loss was also observed with increased MMP-9 activity which was ameliorated by MMP-9 ablation (43). …”