Activation of ELTD1/ADGRL4 induces an endothelial-EMT transition to a pro-angiogenic/myofibroblast-like phenotype.. Activation of ELTD1/ADGRL4 in edothelial cells

ELTD1 is expressed in endothelial and vascular smooth muscle cells and has a role in angiogenesis. It has been classified as an adhesion GPCR, but as yet, no ligand has been identified and its function remains unknown. To establish its role, ELTD1 was expressed in two types of endothelial cells. Expression and consequently ligand independent activation of ELTD1 results in endothelial to mesenchymal transition (EndMT) with a loss of cell-cell contact, formation of stress fibres and mature focal adhesions, and increased expression of smooth muscle actin. The effect was pro-angiogenic, increasing network formation on Matrigel and endothelial sprouting of HMEC-1 cells. Extracellularly tagged ELTD1 localized at the cell surface and live cell imaging captured its strong adhesion to culture plate surfaces and deposition in cell tracks. RNA-Seq analysis of RNA expression at 48hrs and after the cells had undergone EndMT revealed large increases in chemokines and cytokines involved in regulating immune response. Gene set enrichment analysis of the data identified a number of pathways involved in myofibroblast biology. The type II EMT induced is involved in wound repair and is closely associated with inflammation. These data show a new mechanism for EndMT, relevant to it becoming a therapy target.