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Simultaneous activation of several second messengers in hypoxia‐induced hyperpermeability of brain derived endothelial cells
Author(s) -
Fischer Silvia,
Wiesnet Marion,
Marti Hugo H.,
Renz Dieter,
Schaper Wolfgang
Publication year - 2004
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10417
Subject(s) - occludin , microbiology and biotechnology , protein kinase b , pi3k/akt/mtor pathway , tight junction , protein kinase a , mapk/erk pathway , kinase , vascular permeability , second messenger system , endothelial stem cell , biology , signal transduction , chemistry , biochemistry , endocrinology , in vitro
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 Cγ (PLCγ), phosphatidylinositol 3‐kinase/Akt (PI3‐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 PLCγ, PI3‐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 PLCγ and PI3‐K/AKT pathway leading to the activation of PKG. J. Cell. Physiol. 198: 359–369, 2004© 2003 Wiley‐Liss, Inc.