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
  • Mutation
  • Regional Blood Flow
  • Animals
  • Endothelial Cells/metabolism
  • Cell Movement
  • Humans
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Cell Communication
  • Cells, Cultured
  • Pericytes*/metabolism
  • Animals, Genetically Modified
  • Zebrafish*
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
  • Neovascularization, Physiologic*
  • Receptors, CXCR3*/genetics
  • Receptors, CXCR3*/metabolism
  • Angiogenesis
  • Phenotype
  • Chemokine CXCL11*/genetics
  • Chemokine CXCL11*/metabolism
  • Signal Transduction*
  • Coculture Techniques
(all 23)
PubMed
39360413 Full text @ Arterio., Thromb., and Vas. Bio.
Abstract
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.
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.
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.
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)
Show all Figures
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
                    Show
                    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
                    Show
                    Fish
                    No data available
                    Antibodies
                    Name Type Antigen Genes Isotypes Host Organism
                    Ab3-lmnamonoclonal
                      IgG2bMouse
                      Ab9-mapkmonoclonal
                        IgGRabbit
                        Ab11-mapkmonoclonal
                          IgGRabbit
                          Ab17-cdh5polyclonal
                            IgGGoat
                            1 - 4 of 4
                            Show
                            Orthology
                            No data available
                            Engineered Foreign Genes
                            Marker Marker Type Name
                            EGFPEFGEGFP
                            GAL4FFEFGGAL4FF
                            mCherryEFGmCherry
                            TENSEFGTENS
                            TFPEFGTFP
                            VenusEFGVenus
                            1 - 6 of 6
                            Show
                            Mapping
                            No data available