Abstract 13949: Ablation of Matrix Metalloproteinase-9 Mitigates Caveolar Transcytosis in Cerebral Vessels After Mild Traumatic Brain Injury
Traumatic brain injury (TBI) is the most common and major cause of death and disability and significant source of morbidity and mortality for all ages. It is accompanied with activation of matrix metalloproteinase-9 (MMP-9) and increased blood content of inflammatory mediator, fibrinogen (Fg) and is associated with loss of memory. The latter is known to be affected by the level of cellular prion protein (PrPC).
We tested the hypothesis that TBI-induced activation of MMP-9 enhances cerebrovascular leakage leading to Fg extravasation and deposition in subendothelial matrix of microvessels of injury penumbra. High level of deposited Fg contributes to formation of a degradation resistant Fg-PrPC complex and subsequent loss of short memory.
Pial venular leakage of fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) was observed by intravital fluorescence microscopy in male wild-type (WT, C57BL/6J) and MMP-9 gene knockout (MMP9-/-) mice 3 days after a mild TBI. Fg deposition in microvessels of injury penumbra, formation of Fg-PrPC complex, and formation of caveolae defined by co-localization of cavelae markers such as caveolin-1 (Cav-1) and plasmalemma vesicle-associate protein-1 (PV-1), were assessed with immunohistochemistry. Activity of MMP-9 in mouse cortical vessels was defined by in-tissue zymography. Short memory of mice was estimated by a novel object recognition test (NORT).
Leakage of FITC-BSA, Fg deposition, it’s co-localization with PrPC, and caveolae formation were increased after TBI in each experimental group compared to those in respective sham-operated mice. However, they were greater in WT than in MMP9-/- mice. NORT results showed that loss of memory after TBI was greater in WT than in MMP-/- mice.
Thus, our data suggest that TBI-induced cerebrovascular protein leakage via caveolar transcytosis and the resultant Fg deposition leading to increased formation of Fg-PrPC complex and loss of memory were ameliorated in the absence of MMP-9 activity. These results indicate a novel mechanistic role of MMP-9 in post-TBI therapy.
- © 2013 by American Heart Association, Inc.