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Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program

Author

Listed:
  • Maike Frye

    (Uppsala University)

  • Andrea Taddei

    (The Francis Crick Institute)

  • Cathrin Dierkes

    (Max Planck Institute for Molecular Biomedicine)

  • Ines Martinez-Corral

    (Uppsala University)

  • Matthew Fielden

    (Albanova University Center)

  • Henrik Ortsäter

    (Uppsala University)

  • Jan Kazenwadel

    (University of South Australia and SA Pathology)

  • Dinis P. Calado

    (The Francis Crick Institute)

  • Pia Ostergaard

    (St George’s University of London)

  • Marjo Salminen

    (University of Helsinki)

  • Liqun He

    (Tianjin Medical University General Hospital)

  • Natasha L. Harvey

    (University of South Australia and SA Pathology)

  • Friedemann Kiefer

    (Max Planck Institute for Molecular Biomedicine
    University of Münster)

  • Taija Mäkinen

    (Uppsala University)

Abstract

Tissue and vessel wall stiffening alters endothelial cell properties and contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts vascular development is not known. Here we show that matrix stiffness controls lymphatic vascular morphogenesis. Atomic force microscopy measurements in mouse embryos reveal that venous lymphatic endothelial cell (LEC) progenitors experience a decrease in substrate stiffness upon migration out of the cardinal vein, which induces a GATA2-dependent transcriptional program required to form the first lymphatic vessels. Transcriptome analysis shows that LECs grown on a soft matrix exhibit increased GATA2 expression and a GATA2-dependent upregulation of genes involved in cell migration and lymphangiogenesis, including VEGFR3. Analyses of mouse models demonstrate a cell-autonomous function of GATA2 in regulating LEC responsiveness to VEGF-C and in controlling LEC migration and sprouting in vivo. Our study thus uncovers a mechanism by which ECM stiffness dictates the migratory behavior of LECs during early lymphatic development.

Suggested Citation

  • Maike Frye & Andrea Taddei & Cathrin Dierkes & Ines Martinez-Corral & Matthew Fielden & Henrik Ortsäter & Jan Kazenwadel & Dinis P. Calado & Pia Ostergaard & Marjo Salminen & Liqun He & Natasha L. Har, 2018. "Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03959-6
    DOI: 10.1038/s41467-018-03959-6
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    Cited by:

    1. Weiping Dai & Mengqian Yang & Pei Xia & Chuan Xiao & Shuying Huang & Zhan Zhang & Xin Cheng & Wenchang Li & Jian Jin & Jingyun Zhang & Binghuo Wu & Yingying Zhang & Pei-hui Wu & Yangyang Lin & Wen Wu , 2022. "A functional role of meningeal lymphatics in sex difference of stress susceptibility in mice," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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