Tissue Plasminogen Activator Prevents Restoration of Tight Junction Proteins Through Upregulation of Angiopoietin-2

Keisuke      Mishiro; Mitsunori      Ishiguro; Yukiya      Suzuki; Kazuhiro      Tsuruma; Masamitsu      Shimazawa; Hideaki      Hara

doi:10.2174/1567202611310010006

Abstract

We examined the temporal profiles of changes in the expressions of tight junction proteins (TJPs; namely, claudin-5, occludin, and ZO-1) after focal cerebral ischemia/reperfusion in mice. We also examined the effects of delayed treatment with tissue plasminogen activator (tPA) on the expressions of TJPs and angiopoietin (Ang) -1/2/Tie2. Mice subjected to a 6-h filamental middle cerebral artery (MCA) occlusion were treated with tPA (10 mg/kg, intravenously, just after the start of reperfusion) or vehicle. The expressions of TJPs were significantly decreased in the early phase of ischemia/reperfusion, and then gradually recovered. A delayed treatment with tPA decreased the expressions of TJPs when examined at 42 h after reperfusion. In contrast, delayed tPA treatment markedly increased Ang-2, but not Ang-1 expression, when examined at 30 h after reperfusion. Treatment with tPA at 300 g/ml also significantly decreased Ang- 2, but not Tie2 expression, in an in vitro monolayer model generated using human brain microvascular endothelial cells subjected to serum-deprivation. These findings suggest that delayed tPA treatment prevents recovery of TJPs following focal cerebral ischemia/reperfusion, partially via upregulation of Ang-2.

Keywords: Angiopoietin, Blood-brain barrier, Stroke, Tie2, Tight junction proteins, Tissue plasminogen activator

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