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Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling

Author

Listed:
  • Guolun Wang

    (Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center)

  • Bingqiang Wen

    (Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center)

  • Zicheng Deng

    (Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center
    University of Cincinnati)

  • Yufang Zhang

    (Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center)

  • Olena A. Kolesnichenko

    (Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center)

  • Vladimir Ustiyan

    (Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center)

  • Arun Pradhan

    (Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center)

  • Tanya V. Kalin

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati, Cincinnati Children’s Hospital Medical Center)

  • Vladimir V. Kalinichenko

    (Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    University of Cincinnati, Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center)

Abstract

Pulmonary endothelial progenitor cells (EPCs) are critical for neonatal lung angiogenesis and represent a subset of general capillary cells (gCAPs). Molecular mechanisms through which EPCs stimulate lung angiogenesis are unknown. Herein, we used single-cell RNA sequencing to identify the BMP9/ACVRL1/SMAD1 pathway signature in pulmonary EPCs. BMP9 receptor, ACVRL1, and its downstream target genes were inhibited in EPCs from Foxf1WT/S52F mutant mice, a model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Expression of ACVRL1 and its targets were reduced in lungs of ACDMPV subjects. Inhibition of FOXF1 transcription factor reduced BMP9/ACVRL1 signaling and decreased angiogenesis in vitro. FOXF1 synergized with ETS transcription factor FLI1 to activate ACVRL1 promoter. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreased neonatal lung angiogenesis and alveolarization. Treatment with BMP9 restored lung angiogenesis and alveolarization in ACVRL1-deficient and Foxf1WT/S52F mice. Altogether, EPCs promote neonatal lung angiogenesis and alveolarization through FOXF1-mediated activation of BMP9/ACVRL1 signaling.

Suggested Citation

  • Guolun Wang & Bingqiang Wen & Zicheng Deng & Yufang Zhang & Olena A. Kolesnichenko & Vladimir Ustiyan & Arun Pradhan & Tanya V. Kalin & Vladimir V. Kalinichenko, 2022. "Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29746-y
    DOI: 10.1038/s41467-022-29746-y
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    2. Astrid Gillich & Fan Zhang & Colleen G. Farmer & Kyle J. Travaglini & Serena Y. Tan & Mingxia Gu & Bin Zhou & Jeffrey A. Feinstein & Mark A. Krasnow & Ross J. Metzger, 2020. "Capillary cell-type specialization in the alveolus," Nature, Nature, vol. 586(7831), pages 785-789, October.
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