Science and Research

Hypoxia Inducible Factor-1α in SM22α Expressing Cells Modulates Alveolarization

RATIONALE: Worldwide, the incidence of both preterm births and chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD), remains high. Infants with BPD have larger and fewer alveoli, pathology that can persist into adulthood. Though hypoxia inducible factor-1α (HIF-1α) plays a significant role in mediating pulmonary angiogenesis and alveolarization, the cell specific role of HIF-1α remains incompletely understood. OBJECTIVES: To determine whether HIF-1α, in a mesenchymal cells (MC) subset, mediates postnatal alveolarization. METHODS: We generated mice with cell-specific deletion of HIF-1α by crossing SM22α-promoter-driven Cre mice with HIF-1αflox/flox mice (SM22α- HIF-1α(-/-)), determined SM22α-expressing cell identity using single cell RNA-seq, and interrogated clinical samples from preterm infants. Measurement and Main Outcomes: Deletion of HIF-1α in SM22α expressing cells had no effect on lung structure at day (d) 3 of life. However, at 8d there were fewer and larger alveoli, a difference that persisted into adulthood. Microvascular density, elastin organization, and peripheral branching of the lung vasculature were decreased in SM22α-HIF-1α(-/-), compared to control, mice. Single cell RNA-seq demonstrated that 3 MC subtypes (myofibroblasts, airway and vascular smooth muscle cells (VSMC)) express SM22α. Pulmonary VSMC from SM22α- HIF-1α(-/-) had decreased angiopoetin 2 expression and, in co-culture experiments, a diminished capacity to promote angiogenesis that was rescued by angiopoetin-2. Angiopoetin-2 expression in the tracheal aspirates of preterm infants was inversely correlated with overall time on mechanical ventilation, a marker of disease severity. CONCLUSIONS: SM22α-specific HIF-1α expression drives peripheral angiogenesis and alveolarization in the lung, perhaps by promoting angiopoetin-2 expression.

  • Barnes, E. A.
  • Knutsen, C.
  • Kindt, A.
  • Che, X.
  • Ying, L.
  • Adams, E.
  • Gonzalez, E.
  • Oak, P.
  • Hilgendorff, A.
  • Alvira, C. M.
  • Cornfield, D. N.

Keywords

  • alveolarization , oxygen sensing , chronic lung disease of infancy , oxygen
  • sensing, BPD, angiopoietin 2, secondary septation
Publication details
DOI: 10.1165/rcmb.2023-0045OC
Journal: Am J Respir Cell Mol Biol
Work Type: Original
Location: CPC-M
Disease Area: DPLD
Partner / Member: HMGU
Access-Number: 37290124

DZL Engagements

chevron-down