Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling

Abstract

Pulmonary endothelial progenitor cells (EPCs) are critical for neonatal lung angiogenesis and represent a subset of general capillary cells (gCAPs). Molecular mechanisms through which EPCs stimulate lung angiogenesis are unknown. Herein, we used single-cell RNA sequencing to identify the BMP9/ACVRL1/SMAD1 pathway signature in pulmonary EPCs. BMP9 receptor, ACVRL1, and its downstream target genes were inhibited in EPCs from Foxf1WT/S52F mutant mice, a model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Expression of ACVRL1 and its targets were reduced in lungs of ACDMPV subjects. Inhibition of FOXF1 transcription factor reduced BMP9/ACVRL1 signaling and decreased angiogenesis in vitro. FOXF1 synergized with ETS transcription factor FLI1 to activate ACVRL1 promoter. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreased neonatal lung angiogenesis and alveolarization. Treatment with BMP9 restored lung angiogenesis and alveolarization in ACVRL1-deficient and Foxf1WT/S52F mice. Altogether, EPCs promote neonatal lung angiogenesis and alveolarization through FOXF1-mediated activation of BMP9/ACVRL1 signaling.

Histologic Features and Decreased Lung FOXF1 Gene Expression in Severe Bronchopulmonary Dysplasia without a Genetic Diagnosis of Alveolar Capillary Dysplasia

“…13,14 Dysregulation of genes from FOXF1 -related pathways are essential for epithelial branching and vascular patterning, including the lung-specificTMEM100 gene, which is known to be crucial in vascular morphogenesis. 13 Most recently, these data were corroborated in the Foxf1 mouse model, which further demonstrated the role of FOXF1 in mediating endothelial progenitor cell stimulation of angiogenesis via BMP9 signaling 15 Findings from this report support the proposal that in some infants with sBPD, down-regulation of FOXF1 and TMEM100 signaling may contribute to the pathogenesis of severe impairment of lung alveolar and vascular growth, including prominent IBAs with PH.…”

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling

“…The FOXF1 is highly enriched in lung endothelial cells compared to endothelial cells of other organs including liver, pancreas, brain, heart, and kidney 21 , 33 . FOXF1 is required for embryonic development of pulmonary vasculature by activating VEGF, BMP9 and TIE-2 signaling pathways 12 , 16 , 17 . FOXF1 stimulates lung repair and regeneration by regulating genes critical for extracellular matrix remodeling, inflammation, and endothelial barrier function 18 , 25 , 34 – 36 .…”

“…FOXF1 is required for oncogenic properties of PAX3-FOXO1 in rhabdomyosarcoma 15 . In mice, FoxF1 deficiency in EC decreases fetal lung angiogenesis due to inability of FOXF1-deficient ECs to respond to VEGF/FLK1 and BMP9/ACVRL1 signaling 16 , 17 . While FOXF1 induces angiogenesis during embryogenesis, FOXF1 is also expressed in endothelial cells of adult lungs, where angiogenesis is inactive 18 .…”

In vivo generation of bone marrow from embryonic stem cells in interspecies chimeras

“…All raw data and the processed count matrix of BM datasets were uploaded to the GEO database (accession number GSE184940). Read alignments, quality controls, and false discovery rates were described previously ( Guo et al, 2019 ; Ren et al, 2019 ; Wang et al, 2022 ). Identification of cell clusters and quantification of cluster-specific gene expression in BM scRNAseq datasets were performed as described ( Baccin et al, 2020 ; Wang et al, 2021 ; Wen et al, 2021 ).…”