Activation Systems for Latent Matrix Metalloproteinase-2 are Upregulated Immediately after Focal Cerebral Ischemia

Abstract

During focal cerebral ischemia, matrix metalloproteinase-2 (MMP-2) can contribute to the loss of microvessel integrity within ischemic regions by degrading the basal lamina. MMP-2 is secreted in latent form (pro-MMP-2), but the activation of pro-MMP-2 in the ischemic territory has not been shown. Immunohistochemical and in situ hybridization studies of the expression of the direct activators of MMP-2, MT1-MMP and MT3-MMP, and the indirect activation system tissue plasminogen activator, urokinase (u-PA), its receptor (u-PAR), and its inhibitor PAI-1 after middle cerebral artery occlusion/reperfusion were undertaken in basal ganglia samples from 26 adolescent male baboons. The expressions of all three MMPs, u-PA, u-PAR, and PA1-1, but not tissue plasminogen activator, were increased from 1 hour after middle cerebral artery occlusion in the ischemic core. mRNA transcripts confirmed the increases in latent MMP-2, u-PA, u-PAR, and PAI-1 antigen very early after middle cerebral artery occlusion. The expression patterns are consistent with secretion of pro-MMP-2 and its activators in the ischemic core, perhaps from separate cell compartments. The rapid and coordinate appearance of pro-MMP-2 and its activation apparatus suggest that in the primate striatum this protease may participate in matrix injury during focal cerebral ischemia.

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

“…Earlier studies provided indirect evidence that MMP-2 played a key role in the initial opening of the BBB in rat brain (Rosenberg et al, 1998), and in the non-human primate brain (Heo et al, 1999;Chang et al, 2003). We combined in situ zymography, which identified the regions where the gelatinases, either MMP-2 or -9, were active, and gel zymography, which showed that the major form was MMP-2.…”

The Rapid Decrease in Astrocyte-Associated Dystroglycan Expression by Focal Cerebral Ischemia is Protease-Dependent

“…The nature of this MMP-like activity and its source(s) have not been identified. However, pro-MMP-2, pro-MMP-9, MMP-14, MMP-16, and the activators of the latent MMPs (Chang et al, 2003), as well as MMP-3 (Rosenberg et al, 2001), are rapidly expressed in the ischemic regions after MCAO in several model systems.…”

The expression of matrix metalloproteinase-13 is increased in vessels with blood–brain barrier impairment in a stroke-prone hypertensive model

“…[18][19][20] Expression of MMP-9 and MMP-2 has been shown to be significantly increased during stroke in human 21 and animal models of focal ischemia. 19,20,22,23 MMP-9 is of particular interest in the context of acute brain ischemia, because selective upregulation of MMP-9 has been observed in the brains of patients with stroke. 24 Activation of MMP-9 with increased BBB permeability contributes to the early formation of vasogenic edema after focal cerebral ischemia.…”