Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo
Abstract Background Ways 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 un...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-01-01
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| Series: | Fluids and Barriers of the CNS |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12987-021-00302-y |
| _version_ | 1798026276467900416 |
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| author | Julia Baumann Chih-Chieh Tsao Shalmali Patkar Sheng-Fu Huang Simona Francia Synnøve Norvoll Magnussen Max Gassmann Johannes Vogel Christina Köster-Hegmann Omolara O. Ogunshola |
| author_facet | Julia Baumann Chih-Chieh Tsao Shalmali Patkar Sheng-Fu Huang Simona Francia Synnøve Norvoll Magnussen Max Gassmann Johannes Vogel Christina Köster-Hegmann Omolara O. Ogunshola |
| author_sort | Julia Baumann |
| collection | DOAJ |
| description | Abstract Background Ways 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. Methods To 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. Results Unexpectedly, 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. Conclusion This 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. |
| first_indexed | 2024-04-11T18:33:46Z |
| format | Article |
| id | doaj.art-fd3c75ae2fe44f24924b6141781a5127 |
| institution | Directory Open Access Journal |
| issn | 2045-8118 |
| language | English |
| last_indexed | 2024-04-11T18:33:46Z |
| publishDate | 2022-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj.art-fd3c75ae2fe44f24924b6141781a51272022-12-22T04:09:23ZengBMCFluids and Barriers of the CNS2045-81182022-01-0119111710.1186/s12987-021-00302-yPericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivoJulia Baumann0Chih-Chieh Tsao1Shalmali Patkar2Sheng-Fu Huang3Simona Francia4Synnøve Norvoll Magnussen5Max Gassmann6Johannes Vogel7Christina Köster-Hegmann8Omolara O. Ogunshola9Institute of Veterinary Physiology and Center for Clinical Studies, University of ZurichInstitute of Veterinary Physiology and Center for Clinical Studies, University of ZurichInstitute of Veterinary Physiology and Center for Clinical Studies, University of ZurichInstitute of Veterinary Physiology and Center for Clinical Studies, University of ZurichInstitute of Veterinary Physiology and Center for Clinical Studies, University of ZurichInstitute of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of NorwayInstitute of Veterinary Physiology and Center for Clinical Studies, University of ZurichInstitute of Veterinary Physiology and Center for Clinical Studies, University of ZurichInstitute of Veterinary Physiology and Center for Clinical Studies, University of ZurichInstitute of Veterinary Physiology and Center for Clinical Studies, University of ZurichAbstract Background Ways 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. Methods To 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. Results Unexpectedly, 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. Conclusion This 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.https://doi.org/10.1186/s12987-021-00302-yBlood–brain barrierNeurovascular unitPerivascular signalingVascular remodelingCerebral edemaTight junctions |
| spellingShingle | Julia Baumann Chih-Chieh Tsao Shalmali Patkar Sheng-Fu Huang Simona Francia Synnøve Norvoll Magnussen Max Gassmann Johannes Vogel Christina Köster-Hegmann Omolara O. Ogunshola Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo Fluids and Barriers of the CNS Blood–brain barrier Neurovascular unit Perivascular signaling Vascular remodeling Cerebral edema Tight junctions |
| title | Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo |
| title_full | Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo |
| title_fullStr | Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo |
| title_full_unstemmed | Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo |
| title_short | Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo |
| title_sort | pericyte but not astrocyte hypoxia inducible factor 1 hif 1 drives hypoxia induced vascular permeability in vivo |
| topic | Blood–brain barrier Neurovascular unit Perivascular signaling Vascular remodeling Cerebral edema Tight junctions |
| url | https://doi.org/10.1186/s12987-021-00302-y |
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