104
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Endothelial Barrier Antigenimmunoreactivity is Conversely Associated with Blood-Brain Barrier Dysfunction after Embolic Stroke in Rats

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          While the concept of the Neurovascular Unit (NVU) is increasingly considered for exploring mechanisms of tissue damage in ischemic stroke, immunohistochemical analyses are of interest to specifically visualize constituents like the endothelium. Changes in immunoreactivity have also been discussed to reflect functional aspects, e.g., the integrity of the blood-brain barrier (BBB). This study aimed to characterize the endothelial barrier antigen (EBA) as addressed by the antibody SMI-71 in a rat model of embolic stroke, considering FITC-albumin as BBB leakage marker and serum levels of BBB-associated matrix metalloproteinases (MMPs) to explore its functional significance. Five and 25 h after ischemia onset, regions with decreased BBB integrity exhibited a reduction in number and area of EBA-immunopositive vessels, while the stained area per vessel was not affected. Surprisingly, EBA content of remaining vessels tended to be increased in areas of BBB dysfunction. Analyses addressing this interrelation resulted in a significant and inverse correlation between the vessels’ EBA content and degree of BBB permeability. In conclusion, these data provide evidence for a functional relationship between EBA-immunoreactivity and BBB dysfunction in experimental ischemic stroke. Further studies are required to explore the underlying mechanisms of altered EBA-immunoreactivity, which might help to identify novel neuroprotective strategies.

          Related collections

          Most cited references32

          • Record: found
          • Abstract: found
          • Article: not found

          Glial regulation of the cerebral microvasculature.

          The brain is a heterogeneous organ with regionally varied and constantly changing energetic needs. Blood vessels in the brain are equipped with control mechanisms that match oxygen and glucose delivery through blood flow with the local metabolic demands that are imposed by neural activity. However, the cellular bases of this mechanism have remained elusive. A major advance has been the demonstration that astrocytes, cells with extensive contacts with both synapses and cerebral blood vessels, participate in the increases in flow evoked by synaptic activity. Their organization in nonoverlapping spatial domains indicates that they are uniquely positioned to shape the spatial distribution of the vascular responses that are evoked by neural activity. Astrocytic calcium is an important determinant of microvascular function and may regulate flow independently of synaptic activity. The involvement of astrocytes in neurovascular coupling has broad implications for the interpretation of functional imaging signals and for the understanding of brain diseases that are associated with neurovascular dysfunction.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia.

            Regulation of the extracellular matrix by proteases and protease inhibitors is a fundamental biological process for normal growth, development and repair in the CNS. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) are the major extracellular-degrading enzymes. Two other enzyme families, a disintegrin and metalloproteinase (ADAM), and the serine proteases, plasminogen/plasminogen activator (P/PA) system, are also involved in extracellular matrix degradation. Normally, the highly integrated action of these enzyme families remodels all of the components of the matrix and performs essential functions at the cell surface involved in signaling, cell survival, and cell death. During the inflammatory response induced in infection, autoimmune reactions and hypoxia/ischemia, abnormal expression and activation of these proteases lead to breakdown of the extracellular matrix, resulting in the opening of the blood-brain barrier (BBB), preventing normal cell signaling, and eventually leading to cell death. There are several key MMPs and ADAMs that have been implicated in neuroinflammation: gelatinases A and B (MMP-2 and -9), stromelysin-1 (MMP-3), membrane-type MMP (MT1-MMP or MMP-14), and tumor necrosis factor-alpha converting enzyme (TACE). In addition, TIMP-3, which is bound to the cell surface, promotes cell death and impedes angiogenesis. Inhibitors of metalloproteinases are available, but balancing the beneficial and detrimental effects of these agents remains a challenge.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain.

              Reperfusion disrupts cerebral capillaries, causing cerebral edema and hemorrhage. Middle cerebral artery occlusion (MCAO) induces the matrix-degrading metalloproteinases, but their role in capillary injury after reperfusion is unknown. Matrix metalloproteinases (MMPs) and tissue inhibitors to metalloproteinases (TIMPs) modulate capillary permeability. Therefore, we measured blood-brain barrier (BBB) permeability, brain water and electrolytes, MMPs, and TIMPs at multiple times after reperfusion. Adult rats underwent MCAO for 2 hours by the suture method. Brain uptake of 14C-sucrose was measured from 3 hours to 14 days after reperfusion. Levels of MMPs and TIMPs were measured by zymography and reverse zymography, respectively, in contiguous tissues. Other rats had water and electrolytes measured at 3, 24, or 48 hours after reperfusion. Treatment with a synthetic MMP inhibitor, BB-1101, on BBB permeability and cerebral edema was studied. Brain sucrose uptake increased after 3 and 48 hours of reperfusion, with maximal opening at 48 hours and return to normal by 14 days. There was a correlation between the levels of gelatinase A at 3 hours and the sucrose uptake (P<0.05). Gelatinase A (MMP-2) was maximally increased at 5 days, and TIMP-2 was highest at 5 days. Gelatinase B and TIMP-1 were maximally elevated at 48 hours. The inhibitor of gelatinase B, TIMP-1, was also increased at 48 hours. Treatment with BB-1101 reduced BBB opening at 3 hours and brain edema at 24 hours, but neither was affected at 48 hours. The initial opening at 3 hours correlated with gelatinase A levels and was blocked by a synthetic MMP inhibitor. The delayed opening, which was associated with elevated levels of gelatinase B, failed to respond to the MMP inhibitor, suggesting different mechanisms of injury for the biphasic BBB injury.
                Bookmark

                Author and article information

                Journal
                Eur J Histochem
                Eur J Histochem
                EJH
                European Journal of Histochemistry : EJH
                PAGEPress Publications, Pavia, Italy
                1121-760X
                2038-8306
                18 December 2013
                29 October 2013
                : 57
                : 4
                : e38
                Affiliations
                [1 ]Department of Neurology, University of Leipzig
                [2 ]Paul Flechsig Institute for Brain Research, University of Leipzig
                [3 ]Institute of Anatomy, University of Leipzig
                [4 ]Institute of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Leipzig , Germany
                Author notes
                University of Leipzig, Department of Neurology, Liebigstr. 20, 04103 Leipzig, Germany. Tel. +49.341.9724206 - Fax: +49.341.9724199. E-mail: dominik.michalski@ 123456medizin.uni-leipzig.de

                Contributions: DM, CH, WH, conceived the underlying study setup; DS, facilitated funding; DM, CW, conducted animal experiments; JP, WH, performed tissue preparation and serial staining; JP, JK, developed strategy for quantitative analyses; MK, performed additional imaging analyses; JP, analyzed the data; JP, DM, wrote the manuscript; WH, JK, manuscript critical revisions.

                Conflict of interests: the authors declare no conflict of interests.

                Article
                10.4081/ejh.2013.e38
                3896040
                24441191
                4dbdf62b-7fd0-4d10-9643-69b421f38764
                ©Copyright J. Pelz et al.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 May 2013
                : 18 October 2013
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 38, Pages: 7
                Categories
                Original Paper

                Clinical chemistry
                ischemic stroke,blood-brain barrier,matrix metalloproteinase,embolic model,eba
                Clinical chemistry
                ischemic stroke, blood-brain barrier, matrix metalloproteinase, embolic model, eba

                Comments

                Comment on this article