| 1. |
- Jensen, Lasse, et al.
(författare)
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Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of beta-Catenin Signaling
- 2019
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : LIPPINCOTT WILLIAMS & WILKINS. - 1079-5642 .- 1524-4636. ; 39:7, s. 1432-1447
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Tidskriftsartikel (refereegranskat)abstract
- Objective- The Wnt/beta-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/beta-catenin signaling by induced overexpression of Axin1, an inhibitor of beta-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/beta-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, beta-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 beta-catenin-responsive ECM signature was also repressed in Axin1(iEC)-(OE) and endothelial cell-specific beta-catenin-knockout mice (Ctnnb1-KOiEC) during initial blood-brain barrier maturation (E14.5), consistent with an important role of Wnt/beta-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-beta-catenin that impact spatiotemporally on blood-brain barrier differentiation during forebrain vessel development.
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| 2. |
- Schevenels, Giel, et al.
(författare)
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A brain-specific angiogenic mechanism enabled by tip cell specialization
- 2024
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 628:8009, s. 863-871
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Tidskriftsartikel (refereegranskat)abstract
- Vertebrate organs require locally adapted blood vessels1,2. The gain of such organotypic vessel specializations is often deemed to be molecularly unrelated to the process of organ vascularization. Here, opposing this model, we reveal a molecular mechanism for brain-specific angiogenesis that operates under the control of Wnt7a/b ligands—well-known blood–brain barrier maturation signals3,4,5. The control mechanism relies on Wnt7a/b-dependent expression of Mmp25, which we find is enriched in brain endothelial cells. CRISPR–Cas9 mutagenesis in zebrafish reveals that this poorly characterized glycosylphosphatidylinositol-anchored matrix metalloproteinase is selectively required in endothelial tip cells to enable their initial migration across the pial basement membrane lining the brain surface. Mechanistically, Mmp25 confers brain invasive competence by cleaving meningeal fibroblast-derived collagen IV α5/6 chains within a short non-collagenous region of the central helical part of the heterotrimer. After genetic interference with the pial basement membrane composition, the Wnt–β-catenin-dependent organotypic control of brain angiogenesis is lost, resulting in properly patterned, yet blood–brain-barrier-defective cerebrovasculatures. We reveal an organ-specific angiogenesis mechanism, shed light on tip cell mechanistic angiodiversity and thereby illustrate how organs, by imposing local constraints on angiogenic tip cells, can select vessels matching their distinctive physiological requirements.
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