PMID- 35033138 OWN - NLM STAT- MEDLINE DCOM- 20220303 LR - 20220303 IS - 2045-8118 (Electronic) IS - 2045-8118 (Linking) VI - 19 IP - 1 DP - 2022 Jan 15 TI - Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo. PG - 6 LID - 10.1186/s12987-021-00302-y [doi] LID - 6 AB - 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-CreER(T2); HIF-1alpha(fl/fl) and GLAST-CreER(T2); HIF-1alpha(fl/fl)) and pericyte-targeted (SMMHC-CreER(T2); HIF-1alpha(fl/fl)) transgenic animals were generated. Mice in their home cages were exposed to either normoxia (21% O(2)) or hypoxia (8% O(2)) 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-beta 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. CI - (c) 2022. The Author(s). FAU - Baumann, Julia AU - Baumann J AD - Institute of Veterinary Physiology and Center for Clinical Studies, University of Zurich, Vetsuisse Faculty, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. FAU - Tsao, Chih-Chieh AU - Tsao CC AD - Institute of Veterinary Physiology and Center for Clinical Studies, University of Zurich, Vetsuisse Faculty, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. FAU - Patkar, Shalmali AU - Patkar S AD - Institute of Veterinary Physiology and Center for Clinical Studies, University of Zurich, Vetsuisse Faculty, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. FAU - Huang, Sheng-Fu AU - Huang SF AD - Institute of Veterinary Physiology and Center for Clinical Studies, University of Zurich, Vetsuisse Faculty, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. FAU - Francia, Simona AU - Francia S AD - Institute of Veterinary Physiology and Center for Clinical Studies, University of Zurich, Vetsuisse Faculty, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. FAU - Magnussen, Synnove Norvoll AU - Magnussen SN AD - Institute of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromso, Norway. FAU - Gassmann, Max AU - Gassmann M AD - Institute of Veterinary Physiology and Center for Clinical Studies, University of Zurich, Vetsuisse Faculty, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. FAU - Vogel, Johannes AU - Vogel J AD - Institute of Veterinary Physiology and Center for Clinical Studies, University of Zurich, Vetsuisse Faculty, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. FAU - Koster-Hegmann, Christina AU - Koster-Hegmann C AD - Institute of Veterinary Physiology and Center for Clinical Studies, University of Zurich, Vetsuisse Faculty, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. FAU - Ogunshola, Omolara O AU - Ogunshola OO AUID- ORCID: 0000-0002-1197-4914 AD - Institute of Veterinary Physiology and Center for Clinical Studies, University of Zurich, Vetsuisse Faculty, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. larao@access.uzh.ch. LA - eng GR - 31003A_133016/Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung/ GR - 31003A_150062/Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung/ PT - Journal Article DEP - 20220115 PL - England TA - Fluids Barriers CNS JT - Fluids and barriers of the CNS JID - 101553157 RN - 0 (Hypoxia-Inducible Factor 1) SB - IM MH - Animals MH - Astrocytes/*metabolism MH - Capillary Permeability/*physiology MH - Cerebral Cortex/*metabolism MH - Endothelium, Vascular/*metabolism MH - Hypoxia/*metabolism MH - Hypoxia-Inducible Factor 1/*metabolism MH - Mice MH - Mice, Transgenic MH - Pericytes/*metabolism PMC - PMC8760662 OTO - NOTNLM OT - Blood-brain barrier OT - Cerebral edema OT - Endothelium OT - Neurovascular unit OT - Perivascular signaling OT - Tight junctions OT - Vascular remodeling COIS- The authors declare that they have no competing interests. EDAT- 2022/01/17 06:00 MHDA- 2022/03/04 06:00 PMCR- 2022/01/15 CRDT- 2022/01/16 20:33 PHST- 2021/09/02 00:00 [received] PHST- 2021/12/22 00:00 [accepted] PHST- 2022/01/16 20:33 [entrez] PHST- 2022/01/17 06:00 [pubmed] PHST- 2022/03/04 06:00 [medline] PHST- 2022/01/15 00:00 [pmc-release] AID - 10.1186/s12987-021-00302-y [pii] AID - 302 [pii] AID - 10.1186/s12987-021-00302-y [doi] PST - epublish SO - Fluids Barriers CNS. 2022 Jan 15;19(1):6. doi: 10.1186/s12987-021-00302-y.