Simultaneous activation of several second messengers in hypoxia-induced hyperpermeability of brain derived endothelial cells
Simultaneous activation of several second messengers in hypoxia-induced hyperpermeability of brain derived endothelial cells
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DOI：
10.1002/jcp.10417
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发表时间：
2004-03-01
影响因子：
5.6
通讯作者：
Schaper, W
中科院分区：
文献类型：
--
作者：
Fischer, S;Wiesnet, M;Schaper, W
在体内，缺血会损害血脑屏障（BBB），导致血管源性脑水肿的发生。缺氧诱导的血管内皮生长因子（VEGF）已被证明是这些通透性变化的关键调节因子。然而，VEGF 诱导的通透性过高的信号传导途径尚不完全清楚。在这项研究中，我们证明缺氧和 VEGF 诱导的通透性变化取决于磷脂酶 Cgamma (PLCgamma)、磷脂酰肌醇 3-激酶/Akt (P13-K/Akt) 和蛋白激酶 G (PKG) 的激活。丝裂原激活蛋白激酶 (MAPK) 和蛋白激酶 C (PKC) 的抑制根本不影响通透性。与缺氧和 VEGF 诱导的通透性变化平行，缺氧期间紧密连接蛋白 occludin、zonula occlusionns-1 (ZO-1) 和 ZO-2 沿细胞膜的定位从连续表达模式变为更加不连续的表达模式。特别是，ZO-1和ZO-2表达的定位从细胞膜转移到细胞质和细胞核，而occludin表达保留在细胞膜。抑制 PLCgamma、P13 激酶和 PKG 消除了这些缺氧引起的变化。这些发现表明，缺氧和 VEGF 通过内皮连接蛋白的重排诱导通透性，这涉及 PLCgamma 和 P13-K/AKT 通路的激活，从而导致 PKG 的激活。 (C) 2003 Wiley-Liss, Inc.
In vivo, ischemia is known to damage the blood-brain barrier (BBB) leading to the development of vasogenic brain edema. Hypoxia-induced vascular endothelial growth factor (VEGF) has been shown to be a key regulator of these permeability changes. However, the signaling pathways that underlie VEGF-induced hyperpermeability are incompletely understood. In this study, we demonstrate that hypoxia and VEGF-induced permeability changes depend on activation of phospholipase Cgamma (PLCgamma), phosphatidylinositol 3-kinase/Akt (P13-K/Akt), and protein kinase G (PKG). Inhibition of mitogen-activated protein kinases (MAPK) and of the protein kinase C (PKC) did not affect permeability at all. Paralleling hypoxia- and VEGF-induced permeability changes, localization of the tight junction proteins occludin, zonula occludens-1 (ZO-1), and ZO-2 along the cell membrane changed from a continuous to a more discontinuous expression pattern during hypoxia. In particular, localization of ZO-1 and ZO-2 expression moved from the cell membrane to the cytoplasm and nucleus whereas occludin expression remained at the cell membrane. inhibition of PLCgamma, P13-kinase, and PKG abolished these hypoxia-induced changes. These findings demonstrate that hypoxia and VEGF induce permeability through rearrangement of endothelial junctional proteins which involves activation of the PLCgamma and P13-K/AKT pathway leading to the activation of PKG. (C) 2003 Wiley-Liss, Inc.