Division of Pulmonary, Asthma, and Sleep Medicine, Center for Excellence in Pulmonary Biology, and.
Division of Pediatric Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
Am J Respir Cell Mol Biol. 2023 Oct;69(4):470-483. 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.
在全球范围内，早产儿和婴儿期慢性肺部疾病（支气管肺发育不良）的发病率仍然很高。患有支气管肺发育不良的婴儿肺泡更大但数量更少，这种肺部病理变化可能会持续到成年期。尽管最近的数据表明缺氧诱导因子-1α（HIF-1α）在介导肺血管生成和肺泡化中起作用，但 HIF-1α 的细胞特异性作用仍不完全清楚。因此，我们假设 HIF-1α在特定的间充质细胞亚群中介导出生后肺泡化。为了验证这一假设，我们通过将 SM22α 启动子驱动的 Cre 小鼠与 HIF-1α 小鼠杂交，生成了 HIF-1α 细胞特异性缺失的小鼠（SM22α-HIF-1α），使用单细胞 RNA 测序确定 SM-22α 表达细胞的身份，并检测了早产儿的样本。在生命的第 3 天，SM22α 表达细胞中 HIF-1α 的缺失对肺结构没有影响。然而，在第 8 天，肺泡数量减少且更大，这种差异持续到成年期。与对照组相比，SM22α-HIF-1α 小鼠的肺微血管密度、弹性蛋白组织和肺血管周围分支减少。单细胞 RNA 测序表明，三种间充质细胞亚型表达 SM22α：肌成纤维细胞、气道平滑肌细胞和血管平滑肌细胞。SM22α-HIF-1α 小鼠的肺血管平滑肌细胞中血管生成素-2 的表达减少，在共培养实验中，促进血管生成的能力减弱，而血管生成素-2 的表达恢复了这种能力。早产儿气管抽吸物中血管生成素-2 的表达与总机械通气时间呈负相关，这是疾病严重程度的一个标志。我们得出结论，SM22α 特异性 HIF-1α 表达驱动肺外周血管生成和肺泡化，可能通过促进血管生成素-2 的表达。
