Hyperoxia-induced lung microvascular injury is mediated by endothelial cell-derived WNT5A

Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants, with dysmorphic microvascular development being a key factor in the pathogenesis of BPD. WNT5A plays a role in angiogenesis and vascular development and is closely associated with lung disease. This study aimed to investigate the role and underlying mechanism of WNT5A in hyperoxia-induced pulmonary microvascular impairment in BPD.

A hyperoxia exposure mouse model (85% oxygen for 14 days) simulating preterm BPD was used, and was sampled on postnatal day (P) 3, 7, and 14. Western blot (WB) was used to detect the expression of endothelial cell markers von Willebrand factor (vWF) and WNT5A. Mouse pulmonary microvascular endothelial cells (PMVECs) and human umbilical vein endothelial cells (HUVECs) were cultured in 85% oxygen for 48 hours. WNT5A expression and secretion were measured through WB and enzyme-linked immunosorbent assay (ELISA). WNT5A inhibitors or recombinant WNT5A (rWNT5A) were co-cultured with cells, and the cell function was assessed. Total RNA was extracted from PMVECs, followed by RNA sequencing.

WNT5A expression was decreased in the lungs of hyperoxia-exposed mice at P7. Consistently, in vitro hyperoxia exposure reduced WNT5A expression and its downstream effector CaMKIIγ in endothelial cells compared with normoxia-exposed controls. Both WNT5A inhibition and rWNT5A changed the migration and tube formation functions of HUVECs in normoxic and hyperoxic conditions. RNA sequencing revealed differentially expressed genes (DEGs), and suggested enrichment in the ErbB, MAPK, and Hippo pathways in the hyperoxia group.

Hyperoxia decreased the WNT5A expression and impaired endothelial cell function, potentially through WNT5A-CaMKIIγ.