Endothelial specific ERG gene is required for preventing pulmonary vascular complications by regulating sprouting angiogenesis and inflammation

Abstract

ERG, a member of ETS family of transcription factors, acts as a key modulator of endothelial cell differentiation and haematopoiesis. Despite the high degree expression of ERG in endothelial cells, its role in maintaining adult vascular architecture remain elusive. We show that ERG is expressed at the highest level in the adult lung than other vascularized organs such as kidney and brain. Intriguingly, we found that conditional deletion of ERG in endothelial cells of ERGCDh5‐Cre‐ERT mice (ERGiΔEC) spontaneously compromised lung vessel density and these lungs showed severe hemorrhage with vascular injury. The defective angiogenesis was further confirmed by regressed invasive and migratory efficiency of ERG silenced human pulmonary endothelial cells as evaluated by collagen invasion and scratch assay. Further experiments reveled that loss of endothelial ERG markedly reduced several arterial specific genes including DLL4 expression in the lungs and pulmonary ECs. We also found that loss of ERG induced the expression of IL8 and its receptor CXCR2, a critical inducer of inflammation. Immunocytochemistry demonstrated downregulated Dll4 in the sprouting front of the ERG silenced endothelial cells. Dll4 is the only Notch ligand which is expressed predominantly in the vascular endothelium that regulate vascular patterning and vessel density in mature tissues. Ongoing studies are underway to address the linkage between DLL4 with IL8‐mediated inflammatory signalling on vascular pruning and thereby impaired lung functions.