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Mural cell SRF controls pericyte migration, vessel patterning and blood flow

View ORCID ProfileMichael Martin Orlich, Rodrigo Diéguez-Hurtado, Regine Muehlfriedel, Vithiyanjali Sothilingam, Hartwig Wolburg, Cansu Ebru Oender, Pascal Woelffing, Christer Betsholtz, Konstantin Gaengel, Mathias Seeliger, Ralf H. Adams, Alfred Nordheim
doi: https://doi.org/10.1101/2021.11.26.470022
Michael Martin Orlich
1Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany
2International Max Planck Research School (IMPRS) “From Molecules to Organisms”, Tuebingen, Germany
5Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
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  • ORCID record for Michael Martin Orlich
  • For correspondence: michael.orlich@igp.uu.se
Rodrigo Diéguez-Hurtado
6Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Muenster, Germany
7Faculty of Medicine, University of Muenster, Muenster, Germany
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Regine Muehlfriedel
3Institute for Ophthalmic Research, Centre for Ophthalmology, University Clinic Tuebingen (UKT), Tuebingen, Germany
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Vithiyanjali Sothilingam
3Institute for Ophthalmic Research, Centre for Ophthalmology, University Clinic Tuebingen (UKT), Tuebingen, Germany
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Hartwig Wolburg
4Department of General Pathology and Pathological Anatomy, Institute of Pathology and Neuropathology, University Clinic Tuebingen (UKT), Tuebingen, Germany
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Cansu Ebru Oender
1Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany
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Pascal Woelffing
1Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany
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Christer Betsholtz
5Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
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Konstantin Gaengel
5Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
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Mathias Seeliger
3Institute for Ophthalmic Research, Centre for Ophthalmology, University Clinic Tuebingen (UKT), Tuebingen, Germany
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Ralf H. Adams
6Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Muenster, Germany
7Faculty of Medicine, University of Muenster, Muenster, Germany
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Alfred Nordheim
1Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany
2International Max Planck Research School (IMPRS) “From Molecules to Organisms”, Tuebingen, Germany
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Abstract

Rationale Pericytes (PCs) and vascular smooth muscle cells (vSMCs), collectively known as mural cells (MCs), are recruited through PDGFB-PDGFRB signaling. MCs are essential for vascular integrity, and their loss has been associated with numerous diseases. Most of this knowledge is based on studies in which MCs are insufficiently recruited or fully absent upon inducible ablation. In contrast, little is known about the physiological consequences that result from impairment of specific MC functions.

Objective Here, we characterize the role of the transcription factor serum response factor (SRF) in MCs and study its function in developmental and pathological contexts.

Methods and Results We generated a mouse model of MC-specific inducible Srf gene deletion and studied its consequences during retinal angiogenesis. By postnatal day (P)6, PCs lacking SRF were morphologically abnormal and failed to properly co-migrate with angiogenic sprouts. As a consequence, PC-deficient vessels at the retinal sprouting front became dilated and leaky. By P12, also the vSMCs had lost SRF, which coincided with the formation of pathological arteriovenous (AV) shunts. Mechanistically, we show that PDGFB-dependent SRF activation is mediated via MRTF co-factors. We further show that MRTF-SRF signaling promotes pathological PC activation during ischemic retinopathy. RNA-sequencing, immunohistology, in vivo live imaging and in vitro experiments demonstrated that SRF regulates expression of contractile SMC proteins essential to maintain the vascular tone.

Conclusions SRF is crucial for distinct functions in PCs and vSMCs. SRF directs PC migration downstream of PDGFRB signaling and mediates pathological PC activation during ischemic retinopathy. In vSMCs, SRF is essential for expression of the contractile machinery, and its deletion triggers formation of AV shunts. These essential roles in physiological and pathological contexts provide a rational for novel therapeutic approaches through targeting SRF activity in MCs.

Competing Interest Statement

The authors have declared no competing interest.

  • Non-standard Abbreviations and Acronyms

    Actb
    Beta actin
    AV
    arteriovenous
    AVMs
    arteriovenous malformations
    CNS
    Central nervous system
    DEG
    Differential expressed genes
    ECs
    Endothelial cells
    EdU
    5-ethynyl-2’-deoxyuridine
    ERG
    Electroretinography
    FACS
    Fluorescence-activated cell sorting
    fc
    Fold change
    FDR
    False discovery rate
    flex1
    Floxed exon 1
    GO
    Gene ontology
    GSEA
    Gene set enrichment analysis
    ICG
    Indocyanine green
    iMCKO
    Induced mural cell knockout
    kbp
    Kilo base pair
    KEGG
    Kyoto Encyclopedia of Genes and Genomes
    MCs
    Mural cells
    MRTF
    Myocardin related transcription factor
    NG2
    Neural/glial antigen 2
    NVTs
    Neovascular tufts
    OIR
    Oxygen induced retinopathy
    P
    Postnatal day
    pBPCs
    Primary brain pericytes
    PCA
    Principal Component analysis
    PCs
    Pericytes
    PDGFB
    Platelet derived growth factor b
    PDGFRB
    Platelet derived growth factor receptor beta
    RBCs
    Red blood cells
    SLO
    Scanning laser ophthalmoscopy
    SMCs
    Smooth muscle cells
    SMG
    Smooth muscle gene
    SRF
    Serum response factor
    TCFs
    Ternary complex factors
    vSMC
    vascular smooth muscle cell
    αSMA
    Alpha-smooth muscle actin
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted November 27, 2021.
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    Mural cell SRF controls pericyte migration, vessel patterning and blood flow
    Michael Martin Orlich, Rodrigo Diéguez-Hurtado, Regine Muehlfriedel, Vithiyanjali Sothilingam, Hartwig Wolburg, Cansu Ebru Oender, Pascal Woelffing, Christer Betsholtz, Konstantin Gaengel, Mathias Seeliger, Ralf H. Adams, Alfred Nordheim
    bioRxiv 2021.11.26.470022; doi: https://doi.org/10.1101/2021.11.26.470022
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    Mural cell SRF controls pericyte migration, vessel patterning and blood flow
    Michael Martin Orlich, Rodrigo Diéguez-Hurtado, Regine Muehlfriedel, Vithiyanjali Sothilingam, Hartwig Wolburg, Cansu Ebru Oender, Pascal Woelffing, Christer Betsholtz, Konstantin Gaengel, Mathias Seeliger, Ralf H. Adams, Alfred Nordheim
    bioRxiv 2021.11.26.470022; doi: https://doi.org/10.1101/2021.11.26.470022

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