FOXF2 regulates pericyte function required for pericyte-endothelial signaling during neonatal hyperoxic lung injury [scRNA-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: Single-cell RNA sequencing (scRNA-seq) libraries were generated from CD45? cells sorted from control and Foxf2 cKO lungs using the Chromium Next GEM Single Cell 5' Reagent Kit v2 (10x Genomics).