Rapid Differential Endogenous Plasminogen Activator Expression After Acute Middle Cerebral Artery Occlusion

539

449

Summary:Cerebral microvessels have a unique ultrastructure form, which allows for the close relationship of the endothelium and blood elements to the neurons they serve, via intervening astrocytes. To focal ischemia, the cerebral microvasculature rapidly displays multiple dynamic responses. Immediate events include breakdown of the primary endothelial cell permeability barrier, with transudation of plasma, expression of endothelial cell-leukocyte adhesion receptors, loss of endothelial cell and astrocyte integrin receptors, loss of their matrix ligands, expression of members of several matrix-degrading protease families, and the appearance of receptors associated with angiogenesis and neovascularization. These events occur pari passu with neuron injury. Alterations in the microvessel matrix after the onset of ischemia also suggest links to changes in nonvascular cell viability. Microvascular obstruction within the ischemic territory occurs after occlusion and reperfusion of the feeding arteries ("focal no-reflow" phenomenon). This can result from extrinsic compression and intravascular events, including leukocyte(-platelet) adhesion, platelet-fibrin interactions, and activation of coagulation. All of these events occur in microvessels heterogeneously distributed within the ischemic core. The panorama of acute microvessel responses to focal cerebral ischemia provide opportunities to understand interrelationships between neurons and their microvascular supply and changes that underlie a number of central nervous system neurodegenerative disorders.

Section: Effects Of Middle Cerebral Artery Occlusion On the Microvascmentioning

confidence: 93%

Section: Effects Of Middle Cerebral Artery Occlusion On the Microvascmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Cerebral Microvessel Responses to Focal Ischemia

Zoppo

Mabuchi

2003

539

449

“…Other studies also support elevated MMP (elastase and collagenase) activity in ruptured vessels in subarachnoid hemorrhage but not in unruptured aneurysms (Gaetani et al, 1999). MMPs are also involved in the hemorrhagic transformation after cerebral ischemia, especially after thrombolysis (Hosomi et al, 2001;Montaner et al, 2003;Sumii and Lo 2002). Hemorrhagic transformation is closely related to levels of plasma MMP-9 (Castellanos et al, 2003), and MMP inhibitors can reduce hemorrhage after thromboembolic stroke (Lapchak et al, 2000).…”

mentioning

confidence: 92%

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

Tang

Zhou

et al. 2004

159

141

Summary:Matrix metalloproteinase-9 (MMP-9) participates in the disregulation of blood-brain barrier during hemorrhagic transformation, and exacerbates brain injury after cerebral ischemia. However, the consequences of long-term inhibition or deficiency of MMP-9 activity (which might affect normal collagen or matrix homeostasis) remains to be determined. The authors investigated how MMP-9 gene deficiency enhances hemorrhage and increases mortality and neurologic deficits in a collagenase-induced intracerebral hemorrhage (ICH) model in MMP-9-knockout mice. MMP-9-knockout and corresponding wild-type mice at 20 to 35 weeks were used to model an aged population (because advanced age is a significant risk factor in human ICH). Collagenase VII-S (0.5 L, 0.075 U) was injected into the right basal ganglia in mice and mortality, neurologic deficits, brain edema, and hemorrhage size measured. In addition, MMP-9 activity, brain collagen content, blood coagulation, cerebral arterial structure, and expressions of several MMPs were examined. Increased hemorrhage and brain edema that correlated with higher mortality and neurologic deficits were found in MMP-9-knockout mice. No apparent structural changes were observed in cerebral arteries, even though brain collagen content was reduced in MMP-9-knockout mice. MMP-9-knockout mice did exhibit an enhanced expression of MMP-2 and MMP-3 in response to ICH. The results indicate that a deficiency of MMP-9 gene in mutant mice increases collagenase-induced hemorrhage and the resulting brain injury. The intriguing relationship between MMP-9 deficiency and collagenase-induced ICH may reflect the reduction in collagen content and an enhanced expression of MMP-2 and MMP-3. Key Words: MMP-9-Intracerebral hemorrhage-Collagenase-Edema-Blood-brain barrier-Coagulation.Spontaneous intracerebral hemorrhage (ICH) is one of the most serious stroke events, and results in high mortality and morbidity in patients (Bernardini and DeShaies, 2001;Panagos et al., 2002;Woo and Broderick, 2002). Mortality in ICH is often as high as 50% within the first month after ICH, with 50% of these deaths occurring within 48 hours (Broderick, 1993). The mechanisms of ICH-induced early brain injury (e.g. brain edema) have been investigated (Altumbabic et al., 1998;Del Bigio et al., 1999;Xi et al., 2002); however, the complete etiology of early brain injury in ICH is incompletely understood.Matrix metalloproteinases (MMPs) are involved in the pathogenesis of cerebral vascular disorders, particularly the formation and rupture of aneurysms. For example, pro-MMP-2 has been implicated as a significant component within arterial walls of intracerebral aneurysms that leads to subarachnoid hemorrhage (Todor et al., 1998). Other studies also support elevated MMP (elastase and collagenase) activity in ruptured vessels in subarachnoid hemorrhage but not in unruptured aneurysms (Gaetani et al., 1999). MMPs are also involved in the hemorrhagic transformation after cerebral ischemia, especially after thrombolysis (Hosomi et al., 2001;M...

“…The appearance of cathepsin L together with select MMPs, 3 serine proteases, 18 and other proteases in the ischemic regions indicates the rapidly changing microvessel milieu triggered by focal ischemia. These studies confirm the potential roles that microglia activated during ischemia can have in microvessel damage in the ischemic core.…”

Section: Discussionmentioning

confidence: 99%

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

Kanazawa

Hung

et al. 2015

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.