FOXF2 regulates pericyte function required for pericyte-endothelial signaling during neonatal hyperoxic lung injury [RNA-Seq]

Pulmonary vascular development is essential for alveolarization, and disruption of this process contributes to bronchopulmonary dysplasia (BPD) pulmonary pathology. Proper vascular development requires an orchestration of many cell types within the lung. However, the mechanisms by which pericytes support the endothelium in the postnatal lung remain poorly understood. Here, we identify FOXF2 as a critical transcription factor that governs pericyte maturation and function during postnatal lung development and regeneration. FOXF2 expression in pericytes increases postnatally and is selectively downregulated following neonatal hyperoxic injury. Pdgfrb-CreER mediated Foxf2 deletion in pericytes leads to pericyte hyperplasia, impaired migration, reduced expression of angiogenic factors such as ANGPTL4, and exacerbated alveolar simplification in a neonatal murine model of BPD. Transcriptomic and genomic studies demonstrate that FOXF2 maintains chromatin accessibility at pro-angiogenic loci and modulates paracrine signaling essential for endothelial regeneration. Loss of FOXF2 disrupts pericyte–endothelial crosstalk, impairing angiogenesis and alveolar repair during injury. Our study identifies FOXF2 as a central transcriptional regulator of pericyte-driven vascular niche function in the neonatal lung and underscores the pathogenic role of dysfunctional pericytes in BPD. Overall design: Bulk RNA sequencing was performed on CD140b+ cells, sorted by MACS, isolated from the lungs of Foxf2 KO (Foxf2f/f; Pdgfrb-CreER) and littermate control mice at postnatal day 7.

肺血管发育对肺泡形成至关重要，该过程的紊乱可引发支气管肺发育不良（bronchopulmonary dysplasia, BPD）的肺部病理改变。正常肺血管发育需要肺内多种细胞类型协同配合。然而，产后肺内周细胞（pericyte）支持内皮细胞的具体机制仍尚不明确。本研究鉴定出FOXF2是调控产后肺发育与再生过程中周细胞成熟及功能的关键转录因子（transcription factor）。周细胞内的FOXF2表达在产后阶段上调，并在新生儿高氧损伤后发生选择性下调。在新生儿BPD小鼠模型中，通过Pdgfrb-CreER介导周细胞内Foxf2敲除，可导致周细胞增生、迁移能力受损、血管生成因子（如ANGPTL4）表达降低，并加重肺泡简化。转录组学与基因组学研究表明，FOXF2可维持促血管生成基因座的染色质可及性，并调控内皮细胞再生所必需的旁分泌信号通路。FOXF2缺失会破坏周细胞与内皮细胞间的串扰，损害损伤后的血管生成与肺泡修复功能。本研究证实FOXF2是新生儿肺内周细胞介导的血管微环境（vascular niche）功能的核心转录调控因子，并明确了功能异常的周细胞在BPD发病机制中的关键作用。实验整体设计：于出生后第7天，从Foxf2敲除（Foxf2f/f; Pdgfrb-CreER）小鼠及其同窝对照小鼠的肺组织中分离经磁珠激活细胞分选（magnetic-activated cell sorting, MACS）得到的CD140b+细胞，随后对其开展批量RNA测序（bulk RNA sequencing）。