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Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of β-Catenin Signaling

Jensen, Lasse D.; Hot, Belma; Ramsköld, Daniel; Germano, Raoul F.V.; Yokota, Chika; Giatrellis, Sarantis; Lauschke, Volker M.; Hubmacher, Dirk; Li, Minerva X. LU and Hupe, Mike, et al. (2019) In Arteriosclerosis, Thrombosis, and Vascular Biology 39(7). p.1432-1447
Abstract

Objective- The Wnt/β-catenin pathway orchestrates development of the blood-brain barrier, but the downstream mechanisms involved at different developmental windows and in different central nervous system (CNS) tissues have remained elusive. Approach and Results- Here, we create a new mouse model allowing spatiotemporal investigations of Wnt/β-catenin signaling by induced overexpression of Axin1, an inhibitor of β-catenin signaling, specifically in endothelial cells ( Axin1 iEC- OE). AOE (Axin1 overexpression) in Axin1 iEC- OE mice at stages following the initial vascular invasion of the CNS did not impair angiogenesis but led to premature vascular regression followed by progressive dilation and inhibition of vascular maturation... (More)

Objective- The Wnt/β-catenin pathway orchestrates development of the blood-brain barrier, but the downstream mechanisms involved at different developmental windows and in different central nervous system (CNS) tissues have remained elusive. Approach and Results- Here, we create a new mouse model allowing spatiotemporal investigations of Wnt/β-catenin signaling by induced overexpression of Axin1, an inhibitor of β-catenin signaling, specifically in endothelial cells ( Axin1 iEC- OE). AOE (Axin1 overexpression) in Axin1 iEC- OE mice at stages following the initial vascular invasion of the CNS did not impair angiogenesis but led to premature vascular regression followed by progressive dilation and inhibition of vascular maturation resulting in forebrain-specific hemorrhage 4 days post-AOE. Analysis of the temporal Wnt/β-catenin driven CNS vascular development in zebrafish also suggested that Axin1 iEC- OE led to CNS vascular regression and impaired maturation but not inhibition of ongoing angiogenesis within the CNS. Transcriptomic profiling of isolated, β-catenin signaling-deficient endothelial cells during early blood-brain barrier-development (E11.5) revealed ECM (extracellular matrix) proteins as one of the most severely deregulated clusters. Among the 20 genes constituting the forebrain endothelial cell-specific response signature, 8 ( Adamtsl2, Apod, Ctsw, Htra3, Pglyrp1, Spock2, Ttyh2, and Wfdc1) encoded bona fide ECM proteins. This specific β-catenin-responsive ECM signature was also repressed in Axin1 iEC- OE and endothelial cell-specific β-catenin-knockout mice ( Ctnnb1-KOiEC) during initial blood-brain barrier maturation (E14.5), consistent with an important role of Wnt/β-catenin signaling in orchestrating the development of the forebrain vascular ECM. Conclusions- These results suggest a novel mechanism of establishing a CNS endothelium-specific ECM signature downstream of Wnt-β-catenin that impact spatiotemporally on blood-brain barrier differentiation during forebrain vessel development. Visual Overview- An online visual overview is available for this article.

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keywords
basement membrane, blood-brain barrier, central nervous system, embryonic development, endothelial cells, extracellular matrix, vasculature
in
Arteriosclerosis, Thrombosis, and Vascular Biology
volume
39
issue
7
pages
16 pages
publisher
Lippincott Williams Wilkins Hagerstown, MD
external identifiers
  • scopus:85068894784
ISSN
1524-4636
DOI
10.1161/ATVBAHA.119.312388
language
English
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yes
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dd004f7d-31a5-4193-ac94-3f225200bc62
date added to LUP
2019-07-23 13:42:07
date last changed
2019-08-28 04:57:09
@article{dd004f7d-31a5-4193-ac94-3f225200bc62,
  abstract     = {<p>Objective- The Wnt/β-catenin pathway orchestrates development of the blood-brain barrier, but the downstream mechanisms involved at different developmental windows and in different central nervous system (CNS) tissues have remained elusive. Approach and Results- Here, we create a new mouse model allowing spatiotemporal investigations of Wnt/β-catenin signaling by induced overexpression of Axin1, an inhibitor of β-catenin signaling, specifically in endothelial cells ( Axin1 iEC- OE). AOE (Axin1 overexpression) in Axin1 iEC- OE mice at stages following the initial vascular invasion of the CNS did not impair angiogenesis but led to premature vascular regression followed by progressive dilation and inhibition of vascular maturation resulting in forebrain-specific hemorrhage 4 days post-AOE. Analysis of the temporal Wnt/β-catenin driven CNS vascular development in zebrafish also suggested that Axin1 iEC- OE led to CNS vascular regression and impaired maturation but not inhibition of ongoing angiogenesis within the CNS. Transcriptomic profiling of isolated, β-catenin signaling-deficient endothelial cells during early blood-brain barrier-development (E11.5) revealed ECM (extracellular matrix) proteins as one of the most severely deregulated clusters. Among the 20 genes constituting the forebrain endothelial cell-specific response signature, 8 ( Adamtsl2, Apod, Ctsw, Htra3, Pglyrp1, Spock2, Ttyh2, and Wfdc1) encoded bona fide ECM proteins. This specific β-catenin-responsive ECM signature was also repressed in Axin1 iEC- OE and endothelial cell-specific β-catenin-knockout mice ( Ctnnb1-KOiEC) during initial blood-brain barrier maturation (E14.5), consistent with an important role of Wnt/β-catenin signaling in orchestrating the development of the forebrain vascular ECM. Conclusions- These results suggest a novel mechanism of establishing a CNS endothelium-specific ECM signature downstream of Wnt-β-catenin that impact spatiotemporally on blood-brain barrier differentiation during forebrain vessel development. Visual Overview- An online visual overview is available for this article.</p>},
  author       = {Jensen, Lasse D. and Hot, Belma and Ramsköld, Daniel and Germano, Raoul F.V. and Yokota, Chika and Giatrellis, Sarantis and Lauschke, Volker M. and Hubmacher, Dirk and Li, Minerva X. and Hupe, Mike and Arnold, Thomas D. and Sandberg, Rickard and Frisén, Jonas and Trusohamn, Marta and Martowicz, Agnieszka and Wisniewska-Kruk, Joanna and Nyqvist, Daniel and Adams, Ralf H. and Apte, Suneel S. and Vanhollebeke, Benoit and Stenman, Jan M. and Kele, Julianna},
  issn         = {1524-4636},
  keyword      = {basement membrane,blood-brain barrier,central nervous system,embryonic development,endothelial cells,extracellular matrix,vasculature},
  language     = {eng},
  number       = {7},
  pages        = {1432--1447},
  publisher    = {Lippincott Williams  Wilkins Hagerstown, MD},
  series       = {Arteriosclerosis, Thrombosis, and Vascular Biology},
  title        = {Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of β-Catenin Signaling},
  url          = {http://dx.doi.org/10.1161/ATVBAHA.119.312388},
  volume       = {39},
  year         = {2019},
}