Dataset Information

Hypoxia-inducible factor/MAZ-dependent induction of caveolin-1 regulates colon permeability through suppression of occludin, leading to hypoxia-induced inflammation.

ABSTRACT: Caveolae are specialized microdomains on membranes that are critical for signal transduction, cholesterol transport, and endocytosis. Caveolin-1 (CAV1) is a multifunctional protein and a major component of caveolae. Cav1 is directly activated by hypoxia-inducible factor (HIF). HIFs are heterodimers of an oxygen-sensitive ? subunit, HIF1? or HIF2?, and a constitutively expressed ? subunit, aryl hydrocarbon receptor nuclear translocator (ARNT). Whole-genome expression analysis demonstrated that Cav1 is highly induced in mouse models of constitutively activated HIF signaling in the intestine. Interestingly, Cav1 was increased only in the colon and not in the small intestine. Currently, the mechanism and role of HIF induction of CAV1 in the colon are unclear. In mouse models, mice that overexpressed HIF1? or HIF2? specifically in intestinal epithelial cells demonstrated an increase in Cav1 gene expression in the colon but not in the duodenum, jejunum, or ileum. HIF2? activated the Cav1 promoter in a HIF response element-independent manner. myc-associated zinc finger (MAZ) protein was essential for HIF2? activation of the Cav1 promoter. Hypoxic induction of CAV1 in the colon was essential for intestinal barrier integrity by regulating occludin expression. This may provide an additional mechanism by which chronic hypoxia can activate intestinal inflammation.

SUBMITTER: Xie L

PROVIDER: S-EPMC4135598 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Hypoxia-inducible factor/MAZ-dependent induction of caveolin-1 regulates colon permeability through suppression of occludin, leading to hypoxia-induced inflammation.

Xie Liwei L Xue Xiang X Taylor Matthew M Ramakrishnan Sadeesh K SK Nagaoka Kenjiro K Hao Cathy C Gonzalez Frank J FJ Shah Yatrik M YM

Molecular and cellular biology 20140602 16

Caveolae are specialized microdomains on membranes that are critical for signal transduction, cholesterol transport, and endocytosis. Caveolin-1 (CAV1) is a multifunctional protein and a major component of caveolae. Cav1 is directly activated by hypoxia-inducible factor (HIF). HIFs are heterodimers of an oxygen-sensitive α subunit, HIF1α or HIF2α, and a constitutively expressed β subunit, aryl hydrocarbon receptor nuclear translocator (ARNT). Whole-genome expression analysis demonstrated that Ca ...[more]

PMID: 24891620

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Project description:BackgroundWays to prevent disease-induced vascular modifications that accelerate brain damage remain largely elusive. Improved understanding of perivascular cell signalling could provide unparalleled insight as these cells impact vascular stability and functionality of the neurovascular unit as a whole. Identifying key drivers of astrocyte and pericyte responses that modify cell-cell interactions and crosstalk during injury is key. At the cellular level, injury-induced outcomes are closely entwined with activation of the hypoxia-inducible factor-1 (HIF-1) pathway. Studies clearly suggest that endothelial HIF-1 signalling increases blood-brain barrier permeability but the influence of perivascular HIF-1 induction on outcome is unknown. Using novel mouse lines with astrocyte and pericyte targeted HIF-1 loss of function, we herein show that vascular stability in vivo is differentially impacted by perivascular hypoxia-induced HIF-1 stabilization.MethodsTo facilitate HIF-1 deletion in adult mice without developmental complications, novel Cre-inducible astrocyte-targeted (GFAP-CreERT2; HIF-1αfl/fl and GLAST-CreERT2; HIF-1αfl/fl) and pericyte-targeted (SMMHC-CreERT2; HIF-1αfl/fl) transgenic animals were generated. Mice in their home cages were exposed to either normoxia (21% O2) or hypoxia (8% O2) for 96 h in an oxygen-controlled humidified glove box. All lines were similarly responsive to hypoxic challenge and post-Cre activation showed significantly reduced HIF-1 target gene levels in the individual cells as predicted.ResultsUnexpectedly, hypoxia-induced vascular remodelling was unaffected by HIF-1 loss of function in the two astrocyte lines but effectively blocked in the pericyte line. In correlation, hypoxia-induced barrier permeability and water accumulation were abrogated only in pericyte targeted HIF-1 loss of function mice. In contrast to expectation, brain and serum levels of hypoxia-induced VEGF, TGF-β and MMPs (genes known to mediate vascular remodelling) were unaffected by HIF-1 deletion in all lines. However, in agreement with the permeability data, immunofluorescence and electron microscopy showed clear prevention of hypoxia-induced tight junction disruption in the pericyte loss of function line.ConclusionThis study shows that pericyte but not astrocyte HIF-1 stabilization modulates endothelial tight junction functionality and thereby plays a pivotal role in hypoxia-induced vascular dysfunction. Whether the cells respond similarly or differentially to other injury stimuli will be of significant relevance.

Dataset Information

Hypoxia-inducible factor/MAZ-dependent induction of caveolin-1 regulates colon permeability through suppression of occludin, leading to hypoxia-induced inflammation.

Publications

Hypoxia-inducible factor/MAZ-dependent induction of caveolin-1 regulates colon permeability through suppression of occludin, leading to hypoxia-induced inflammation.

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