FOXF2 regulates pericyte-endothelial signaling required for vascular homeostasis after neonatal hyperoxic lung injury.

Abstract

Pulmonary vascular development is essential for alveolarization, and disruption of this process contributes to pathogenesis of bronchopulmonary dysplasia (BPD). Proper vascular development requires an orchestration of many cell types within the lung. However, the transcriptional mechanisms by which pericytes support the endothelium in the postnatal lung remain poorly understood. Herein, 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 after neonatal hyperoxic injury. Pdgfrb-CreER mediated Foxf2 deletion in pericytes leads to pericyte hyperplasia, impaired migration, and reduced expression of angiogenic factors such as ANGPTL4. 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, leading to impaired angiogenesis and alveolarization as well as increased vascular permeability after neonatal lung injury. Altogether, FOXF2 acts as a key transcriptional regulator of the pericyte-driven vascular niche in the neonatal lung, highlighting the pathogenic role of pericyte dysfunction in BPD.