Microvascular Basal Lamina Antigens Disappear During Cerebral Ischemia and Reperfusion

Hamann, Gerhard F.; Okada, Yasushi; Fitridge, Robert; Zoppo, Gregory J. del

doi:10.1161/01.str.26.11.2120

Cited by 327 publications

(299 citation statements)

References 41 publications

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“…MMPs degrade the components of the basal lamina, namely, heparan sulfate, laminin, fibronectin, and type IV collagen. During cellular stress from ischemia/hypoxia, the macromolecules of the basal lamina are reduced, presumably by the action of the ECM-degrading proteases, and loss of the matrix increases the rate of hemorrhage (Hamann et al, 1995). Pericytes are macrophage-like cells that are found next to the endothelial cells and are surrounded by basal lamina.…”

Section: Role Of the Mmps In Neuroinflammation In Cerebral Ischemiamentioning

confidence: 99%

Matrix metalloproteinases in neuroinflammation

Rosenberg

2002

Glia

781

667

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Matrix metalloproteinases (MMPs) are a gene family of neutral proteases that are important in normal development, wound healing, and a wide variety of pathological processes, including the spread of metastatic cancer cells, arthritic destruction of joints, atherosclerosis, and neuroinflammation. In the central nervous system (CNS), MMPs have been shown to degrade components of the basal lamina, leading to disruption of the blood-brain barrier (BBB), and to contribute to the neuroinflammatory response in many neurological diseases. Brain cells express both constitutive and inducible MMPs in response to cellular stress. MMPs are tightly regulated to avoid unwanted proteolysis. Secreted as inactive enzymes, the MMPs require activation by other proteases and free radicals. The MMPs are part of a larger class of metalloproteinases (MPs), which includes the recently discovered ADAMs (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase thrombospondin) families. MPs have complex roles at the cell surface and within the extracellular matrix. At the cell surface, they act as sheddases, releasing growth factors, death receptors, and death-inducing ligands, making them important in cell survival and death. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that regulate the activity of the MMPs. Synthetic inhibitors have been developed for the treatment of arthritis and cancer. These hydroxymate-based compounds have been shown to reduce injury in experimental allergic encephalomyelitis (EAE), experimental allergic neuritis (EAN), cerebral ischemia, intracerebral hemorrhage, and viral and bacterial infections. MPs have both beneficial and detrimental roles; understanding their expression in various CNS insults will allow for the use of MMP inhibitors in the treatment of neurological disorders. GLIA 39: 279 -291, 2002.

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Section: Role Of the Mmps In Neuroinflammation In Cerebral Ischemiamentioning

confidence: 99%

Matrix metalloproteinases in neuroinflammation

Rosenberg

2002

Glia

781

667

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“…The TJPs include zona occludens (ZOs) proteins in the endothelial cells, while in the endothelial cell clefts are found occludin and claudins (Furuse et al, 1993(Furuse et al, , 1998Morita et al, 1999a;Nitta et al, 2003). Proteases of the serine and matrix metalloproteinase (MMP) gene families have been shown to degrade proteins of the basal lamina around the cerebral blood vessels (Hamann et al, 1995;Fukuda et al, 2004). An earlier study showed that gelatinase B (MMP-9) degrades ZOs in focal ischemia (Asahi et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinase-Mediated Disruption of Tight Junction Proteins in Cerebral Vessels is Reversed by Synthetic Matrix Metalloproteinase Inhibitor in Focal Ischemia in Rat

Yang

Estrada

Thompson

et al. 2007

J Cereb Blood Flow Metab

920

772

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Matrix metalloproteinases (MMPs) disrupt the blood-brain barrier (BBB) during reperfusion. Occludin and claudins are recently described tight junction proteins (TJPs) that form the BBB. We hypothesized that the opening of the BBB was because of the degradation of TJPs by the MMPs. Spontaneously hypertensive rats had a 90 mins middle cerebral artery occlusion with reperfusion for 2, 3, or 24 h. Matrix metalloproteinases were measured by immunohistochemistry and in situ and gel zymography. Real-time polymerase chain reaction (PCR) measured mRNAs of MMP-2 and -9, furin, membrane-type MMP (MT1-MMP), occludin, and claudin-5. There was opening of the BBB in the piriform cortex after 3 h of reperfusion, and an MMP inhibitor, BB-1101 (30 mg/kg), prevented the opening. At 3 h, in situ zymograms showed gelatinase activity. Zymography and PCR showed greater increases in MMP-2 than in MMP-9. There were increased mRNA and immunohistochemistry for MT1-MMP and furin, which activate MMP-2. Claudin-5 and occludin mRNA expression decreased at 2 h in both hemispheres with fragments of both proteins seen on Western blot by 3 h on the ischemic side; treatment with BB-1101 reversed the degradation of the TJPs. Immunohistochemistry at 3 h showed fragmented TJPs within the endothelial cell clefts. By 24 h, in situ zymography showed gelatinase activity and gel zymography showed elevated levels of MMP-9. Disrupted TJPs previously seen in endothelial cells appeared in the surrounding astrocytes. Our results provide direct evidence that MMPs open the BBB by degrading TJPs and that an MMP inhibitor prevents degradation of the TJPs by MMPs.

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“…Within 1-2 hours after MCAO, in the non-human primate, significant changes in laminin, collagen IV, FN, and perlecan occur within microvessel basal lamina matrix in the ischemic core. 1,2 Knowing how acute changes in microvessel matrix architecture occur quantitatively, the contributions of individual matrix proteases, and their specific cell sources are central to devising methods for preservation of microvessel and neurovascular unit integrity, and for reducing hemorrhagic transformation. 1,26 These studies were prompted by the observation in the non-human primate of acute cathepsin L protein and activity expression in the neurovascular unit coincident with the simultaneous disappearance of its substrates perlecan and collagen IV in the microvasculature.…”

Section: Discussionmentioning

confidence: 99%

“…5 However, the rapid appearance of cathepsin L also coincides with the loss of other microvessel ECM components in non-human primate, and the appearance of (pro-)MMP-2. 1,3 This suggests that very early during focal ischemia one or more matrix proteases may degrade perlecan, as well as the major structural components of the basal lamina ECM. In addition, cathepsins L and B are known to degrade the substrates and major ECM components collagen IV, laminin, and fibronectin (FN) in vitro.…”

Section: Introductionmentioning

confidence: 99%

Cathepsin L Acutely Alters Microvessel Integrity within the Neurovascular Unit during Focal Cerebral Ischemia

Kanazawa

Hung

et al. 2015

J Cereb Blood Flow Metab

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During focal cerebral ischemia, the degradation of microvessel basal lamina matrix occurs acutely and is associated with edema formation and microhemorrhage. These events have been attributed to matrix metalloproteinases (MMPs). However, both known protease generation and ligand specificities suggest other participants. Using cerebral tissues from a non-human primate focal ischemia model and primary murine brain endothelial cells, astrocytes, and microglia in culture, the effects of active cathepsin L have been defined. Within 2 hours of ischemia onset cathepsin L, but not cathepsin B, activity appears in the ischemic core, around microvessels, within regions of neuron injury and cathepsin L expression. In in vitro studies, cathepsin L activity is generated during experimental ischemia in microglia, but not astrocytes or endothelial cells. In the acidic ischemic core, cathepsin L release is significantly increased with time. A novel ex vivo assay showed that cathepsin L released from microglia during ischemia degrades microvessel matrix, and interacts with MMP activity. Hence, the loss of microvessel matrix during ischemia is explained by microglial cathepsin L release in the acidic core during injury evolution. The roles of cathepsin L and its interactions with specific MMP activities during ischemia are relevant to strategies to reduce microvessel injury and hemorrhage.

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Microvascular Basal Lamina Antigens Disappear During Cerebral Ischemia and Reperfusion

Abstract: The significant parallel losses of three basal lamina components, both in number and intensity, contribute to loss of microvascular integrity. These phenomena may be important for understanding cell extravasation and the hemorrhagic consequences of acute stroke.

Cited by 327 publications

References 41 publications

Matrix metalloproteinases in neuroinflammation

Matrix metalloproteinases in neuroinflammation

Matrix Metalloproteinase-Mediated Disruption of Tight Junction Proteins in Cerebral Vessels is Reversed by Synthetic Matrix Metalloproteinase Inhibitor in Focal Ischemia in Rat

Cathepsin L Acutely Alters Microvessel Integrity within the Neurovascular Unit during Focal Cerebral Ischemia

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