Impact of Fgf10 deficiency on pulmonary vasculature formation in a mouse model of bronchopulmonary dysplasia

Abstract

Bronchopulmonary dysplasia (BPD), characterized by alveoli simplification and dysmorphic pulmonary microvasculature, is a chronic lung disease affecting prematurely born infants. Pulmonary hypertension (PH) is an important BPD feature associated with morbidity and mortality. In human BPD, inf lammation leads to decreased fibroblast growth factor 10 (FGF10) expression but the impact on the vasculature is so far unknown. We used lungs from Fgf10 +/− versus Fgf10 +/+ pups to investigate the effect of Fgf10 deficiency on vascular development in normoxia (NOX) and hyperoxia (HOX, BPD mouse model). To assess the role of fibroblast growth factor receptor 2b (Fgfr2b) ligands independently of early developmental 1430

Targeting Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension (BPD-PH): Potential Role of the FGF Signaling Pathway in the Development of the Pulmonary Vascular System

“…Bhatt et al analyzed lung samples from infants who died with BPD versus infants who died from non-pulmonary causes and found a decreased expression of VEGF and platelet endothelial cell adhesion molecule-1 (PECAM, also termed CD31, endothelial marker), as well as a decreased staining density of alveolar capillaries in BPD infants, indicating that the development of the pulmonary microvasculature was disrupted in BPD patients [ 4 ]. Consistent with previous results, we and others, utilizing BPD animal models, established by hyperoxia exposure, also showed a decrease of endothelial cells in capillaries and blood vessel numbers and an increase of α-Sma positive cells (VSMC) in the tunica media of pulmonary arterioles and normally non-muscularized precapillary arterioles [ 79 , 80 , 81 ]. A lineage tracing study indicated that the expansion of resident SMCs was the major source related to the thickening of the smooth muscle layer in adult PH [ 82 ].…”

“…A BPD-PH animal model needs to be established. It has been shown recently, that blockade of Fgfr2b ligands activity postnatally in a BPD mouse model lead to decreased blood vessel number and increased muscularization resembling a PH-like phenotype [ 79 ].…”

“…More and more research findings which have mainly used preclinical mouse models for lung injury, have confirmed the role of Fgf10 in protecting and regenerating the lung tissue during and after lung injury, e.g., in lung fibrosis [ 115 , 116 , 117 ]. Our recent data emphasized, that Fgf10 indeed plays a crucial role in branching morphogenesis and formation of the pulmonary vasculature during development [ 79 , 118 ]. As previously mentioned, the temporal–spatial proximity of the lung vasculature and the distal epithelium suggests a close interaction between these two important structures via endothelial–epithelial tissue crosstalk.…”

Fgf10 Signaling-Based Evidence for the Existence of an Embryonic Stage Distinct From the Pseudoglandular Stage During Mouse Lung Development

“…From a developmental point of view, this phenotype is caused by impaired formation of secondary septa which are transient structures leading to the subdivision of the sacs into smaller units called alveoli. Our mouse data suggest that Fgf10 is indeed critical for the alveologenesis phase to occur and has also a collateral impact on the formation of the vascular system (Chao et al, 2019). Therefore, while the role of Fgf10 appears to be consistent between human and mouse during alveologenesis, we recently reported that FGF10 displayed a discordant role in lung branching morphogenesis in human and mouse (Danopoulos et al, 2019).…”

Signaling Pathways Involved in the Development of Bronchopulmonary Dysplasia and Pulmonary Hypertension

“…In addition, during embryonic development, mesenchymal cells expressing FGF10 are progenitors for airway and vascular SMC [ 59 ]. VEGFa is a target of FGF10 in developing lung epithelium and the reduction in FGF10 levels leads to decrease in VEGFa and vascular defect [ 60 ]. FGF10 is not only essential for epithelial progenitor cell proliferation but also for coordinated alveolar SMC formation and vascular development [ 61 ].…”