PUBLICATION

CXCR3-CXCL11 Signaling Restricts Angiogenesis and Promotes Pericyte Recruitment

Authors
Lee, J., Goeckel, M.E., Levitas, A., Colijn, S., Shin, J., Hindes, A., Mun, G., Burton, Z., Chintalapati, B., Yin, Y., Abello, J., Solnica-Krezel, L., Stratman, A.
ID
ZDB-PUB-241003-12
Date
2024
Source
Arteriosclerosis, Thrombosis, and Vascular Biology   44(12): 2577-2595 (Journal)
Registered Authors
Abello, Javier, Colijn, Sarah, Goeckel, Megan, Hindes, Anna, Levitas, Alli, Shin, Jimann, Solnica-Krezel, Lilianna, Stratman, Amber, Yin, Ying
Keywords
endothelial cells, gain-of-function mutation, hemodynamics, pericytes, zebra fish
MeSH Terms
  • Neovascularization, Physiologic*
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Animals
  • Zebrafish*
  • Animals, Genetically Modified
  • Cells, Cultured
  • Coculture Techniques
  • Cell Communication
  • Humans
  • Phenotype
  • Endothelial Cells/metabolism
  • Pericytes*/metabolism
  • Chemokine CXCL11*/genetics
  • Chemokine CXCL11*/metabolism
  • Mutation
  • Regional Blood Flow
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
  • Receptors, CXCR3*/genetics
  • Receptors, CXCR3*/metabolism
  • Cell Movement
  • Signal Transduction*
  • Angiogenesis
(all 23)
PubMed
39360413 Full text @ Arterio., Thromb., and Vas. Bio.
Abstract
Background Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces; yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor CXCR3 (CXC motif chemokine receptor 3) and one of its ligands, CXCL11 (CXC motif chemokine ligand 11)-that delimits EC angiogenic potential and promotes pericyte recruitment to ECs during development.
Methods We investigated the role of CXCR3 on vascular development using both 2- and 3-dimensional in vitro assays, to study EC-pericyte interactions and EC behavioral responses to blood flow. Additionally, genetic mutants and pharmacological modulators were used in zebra fish in vivo to study the impacts of CXCR3 loss and gain of function on vascular development.
Results In vitro modeling of EC-pericyte interactions demonstrates that suppression of EC-specific CXCR3 signaling leads to loss of pericyte association with EC tubes. In vivo, phenotypic defects are particularly noted in the cranial vasculature, where we see a loss of pericyte association with ECs and expansion of the vasculature in zebra fish treated with the Cxcr3 inhibitor AMG487 or in homozygous cxcr3.1/3.2/3.3 triple mutants. We also demonstrate that CXCR3-deficient ECs are more elongated, move more slowly, and have impaired EC-EC junctions compared with their control counterparts.
Conclusions Our results suggest that CXCR3 signaling in ECs helps promote vascular stabilization events during development by preventing EC overgrowth and promoting pericyte recruitment.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ncv24TgTransgenic Insertion
    stl10
      		Indel
      stl148
        		Small Deletion
        stl149
          		Small Deletion
          uq11bhTgTransgenic Insertion
            uq37bhTgTransgenic Insertion
              y1TgTransgenic Insertion
                y171TgTransgenic Insertion
                  y530TgTransgenic Insertion
                    1 - 9 of 9
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                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    Target Reagent Reagent Type
                    cxcr3.1TALEN1-cxcr3.1TALEN
                    cxcr3.2TALEN1-cxcr3.2TALEN
                    cxcr3.3TALEN1-cxcr3.3TALEN
                    1 - 3 of 3
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                    Fish
                    No data available
                    Antibodies
                    Orthology
                    No data available
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    EGFPEFGEGFP
                    GAL4FFEFGGAL4FF
                    mCherryEFGmCherry
                    TENSEFGTENS
                    TFPEFGTFP
                    VenusEFGVenus
                    1 - 6 of 6
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                    Mapping
                    No data available
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                    Citation
                    Lee, J., Goeckel, M.E., Levitas, A., Colijn, S., Shin, J., Hindes, A., Mun, G., Burton, Z., Chintalapati, B., Yin, Y., Abello, J., Solnica-Krezel, L., Stratman, A. (2024) CXCR3-CXCL11 Signaling Restricts Angiogenesis and Promotes Pericyte Recruitment. Arteriosclerosis, Thrombosis, and Vascular Biology. 44(12):2577-2595.