PMID- 24375098
OWN - NLM
STAT- MEDLINE
DCOM- 20140721
LR  - 20140423
IS  - 1097-4652 (Electronic)
IS  - 0021-9541 (Linking)
VI  - 229
IP  - 8
DP  - 2014 Aug
TI  - Hypoxia selectively disrupts brain microvascular endothelial tight junction 
      complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism.
PG  - 1096-105
LID - 10.1002/jcp.24544 [doi]
AB  - The blood-brain barrier (BBB) constitutes a critical barrier for the maintenance 
      of central nervous system homeostasis. Brain microvascular endothelial cells line 
      the vessel walls and express tight junction (TJ) complexes that restrict 
      paracellular passage across the BBB, thereby fulfilling a crucial role in 
      ensuring brain function. Hypoxia, an impaired O(2) delivery, is known to cause 
      BBB dysfunction but the mechanisms that drive this disruption remain unclear. 
      This study discloses the relevance of the master regulator of the hypoxic 
      response, hypoxia-inducible factor-1 (HIF-1), in hypoxia-induced barrier 
      disruption using the rat brain endothelial cell line RBE4. Hypoxic exposure 
      rapidly induced stabilization of the HIF-1 oxygen-dependent alpha subunit 
      (HIF-1alpha) concomitantly with BBB impairment and TJ disruption mainly through 
      delocalization and increased tyrosine phosphorylation of TJ proteins. Similar 
      observations were obtained by normoxic stabilization of HIF-1alpha using CoCl(2), 
      deferoxamine, and dimethyloxalylglycine underlining the involvement of HIF-1 in 
      barrier dysfunction particularly via TJ alterations. In agreement inhibition of 
      HIF-1 stabilization by 2-methoxyestradiol and YC-1 improved barrier function in 
      hypoxic cells. Overall our data suggests that activation of HIF-1-mediated 
      signaling disrupts TJ resulting in increased BBB permeability.
CI  - (c) 2014 Wiley Periodicals, Inc.
FAU - Engelhardt, Sabrina
AU  - Engelhardt S
AD  - Vetsuisse Faculty, Institute of Veterinary Physiology & Zurich Center Integrative 
      Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
FAU - Al-Ahmad, Abraham J
AU  - Al-Ahmad AJ
FAU - Gassmann, Max
AU  - Gassmann M
FAU - Ogunshola, Omolara O
AU  - Ogunshola OO
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (Hif1a protein, rat)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Tight Junction Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Survival
MH  - Endothelial Cells/*drug effects/*physiology
MH  - Gene Expression Regulation/drug effects
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Oxygen/*metabolism/pharmacology
MH  - Phosphorylation
MH  - Rats
MH  - Signal Transduction/drug effects
MH  - Tight Junction Proteins/genetics/*metabolism
MH  - Vascular Endothelial Growth Factor A/genetics/metabolism
EDAT- 2014/01/01 06:00
MHDA- 2014/07/22 06:00
CRDT- 2013/12/31 06:00
PHST- 2013/06/27 00:00 [received]
PHST- 2013/12/17 00:00 [accepted]
PHST- 2013/12/31 06:00 [entrez]
PHST- 2014/01/01 06:00 [pubmed]
PHST- 2014/07/22 06:00 [medline]
AID - 10.1002/jcp.24544 [doi]
PST - ppublish
SO  - J Cell Physiol. 2014 Aug;229(8):1096-105. doi: 10.1002/jcp.24544.