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Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity

Author

Listed:
  • Sara G. Romeo

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Ilaria Secco

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Edoardo Schneider

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Christina M. Reumiller

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Celio X. C. Santos

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Anna Zoccarato

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Vishal Musale

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Aman Pooni

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Xiaoke Yin

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Konstantinos Theofilatos

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Silvia Cellone Trevelin

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Lingfang Zeng

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Giovanni E. Mann

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Varun Pathak

    (Queen’s University Belfast)

  • Kevin Harkin

    (Queen’s University Belfast)

  • Alan W. Stitt

    (Queen’s University Belfast)

  • Reinhold J. Medina

    (Queen’s University Belfast)

  • Andriana Margariti

    (Queen’s University Belfast)

  • Manuel Mayr

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Ajay M. Shah

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Mauro Giacca

    (School of Cardiovascular & Metabolic Medicine and Sciences)

  • Anna Zampetaki

    (School of Cardiovascular & Metabolic Medicine and Sciences)

Abstract

The microvasculature plays a key role in tissue perfusion and exchange of gases and metabolites. In this study we use human blood vessel organoids (BVOs) as a model of the microvasculature. BVOs fully recapitulate key features of the human microvasculature, including the reliance of mature endothelial cells on glycolytic metabolism, as concluded from metabolic flux assays and mass spectrometry-based metabolomics using stable tracing of 13C-glucose. Pharmacological targeting of PFKFB3, an activator of glycolysis, using two chemical inhibitors results in rapid BVO restructuring, vessel regression with reduced pericyte coverage. PFKFB3 mutant BVOs also display similar structural remodelling. Proteomic analysis of the BVO secretome reveal remodelling of the extracellular matrix and differential expression of paracrine mediators such as CTGF. Treatment with recombinant CTGF recovers microvessel structure. In this work we demonstrate that BVOs rapidly undergo restructuring in response to metabolic changes and identify CTGF as a critical paracrine regulator of microvascular integrity.

Suggested Citation

  • Sara G. Romeo & Ilaria Secco & Edoardo Schneider & Christina M. Reumiller & Celio X. C. Santos & Anna Zoccarato & Vishal Musale & Aman Pooni & Xiaoke Yin & Konstantinos Theofilatos & Silvia Cellone Tr, 2023. "Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41326-2
    DOI: 10.1038/s41467-023-41326-2
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