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

• Published in: American journal of respiratory cell and molecular biology Vol. 69; no. 4; pp. 470 - 483
• Main Authors: Barnes, Elizabeth A, Knutsen, Carsten, Kindt, Alida, Che, Xibing, Ying, Lihua, Adams, Eloa, Gonzalez, Erika, Oak, Prajakta, Hilgendorff, Anne, Alvira, Cristina M, Cornfield, David N
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.10.2023
• Subjects: Angiogenesis; Angiopoietin-2 - metabolism; Animals; Bronchopulmonary Dysplasia - genetics; Bronchopulmonary Dysplasia - metabolism; Bronchopulmonary Dysplasia - pathology; Dysplasia; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Infant, Newborn; Infant, Premature; Lung - pathology; Lung diseases; Mesenchyme; Mice; Original Research; Premature babies; Premature birth; angiopoietin-2; oxygen sensing; bronchopulmonary dysplasia; lung development
• ISSN: 1044-1549; 1535-4989; 1535-4989
• DOI: 10.1165/rcmb.2023-0045OC

Worldwide, the incidence of both preterm births and chronic lung disease of infancy, or bronchopulmonary dysplasia, remains high. Infants with bronchopulmonary dysplasia have larger and fewer alveoli, a lung pathology that can persist into adulthood. Although recent data point to a role for hypoxia-inducible factor-1α (HIF-1α) in mediating pulmonary angiogenesis and alveolarization, the cell-specific role of HIF-1α remains incompletely understood. Thus, we hypothesized that HIF-1α, in a distinct subset of mesenchymal cells, mediates postnatal alveolarization. To test the hypothesis, we generated mice with a cell-specific deletion of HIF-1α by crossing SM22α promoter-driven Cre mice with HIF-1α mice (SM22α-HIF-1α ), determined SM-22α-expressing cell identity using single-cell RNA sequencing, and interrogated samples from preterm infants. Deletion of HIF-1α in SM22α-expressing cells had no effect on lung structure at day 3 of life. However, at 8 days, 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 mice, compared with control mice. Single-cell RNA sequencing demonstrated that three mesenchymal cell subtypes express SM22α: myofibroblasts, airway smooth muscle cells, and vascular smooth muscle cells. Pulmonary vascular smooth muscle cells from SM22α-HIF-1α mice had decreased angiopoietin-2 expression and, in coculture experiments, a diminished capacity to promote angiogenesis that was rescued by angiopoietin-2. Angiopoietin-2 expression in tracheal aspirates of preterm infants was inversely correlated with overall mechanical ventilation time, a marker of disease severity. We conclude that SM22α-specific HIF-1α expression drives peripheral angiogenesis and alveolarization in the lung, perhaps by promoting angiopoietin-2 expression.