The Bipartite Rac1 Guanine Nucleotide Exchange Factor Engulfment and Cell Motility 1/Dedicator of Cytokinesis 180 (Elmo1/Dock180) Protects Endothelial Cells from Apoptosis in Blood Vessel Development

Engulfment and cell motility 1/dedicator of cytokinesis 180 (Elmol/Dock180) is a bipartite guanine nucleotide exchange factor for the monomeric GTPase Ras-related C3 botulinum toxin substrate 1 (Racl). Elmol/Dock180 regulates Racl activity in a specific spatiotemporal manner in endothelial cells (ECs) during zebrafish development and acts downstream of the Netrin-1/Unc5-homolog B (Unc5B) signaling cascade. However, mechanistic details on the pathways by which Elmol/ Dock 180 regulates endothelial function and vascular development remained elusive. In this study, we aimed to analyze the vascular function of Elmol and Dock180 in human ECs and during vascular development in zebrafish embryos. In vitro overexpression of Elmol and Dock180 in ECs reduced caspase-3/7 activity and annexin V-positive cell number upon induction of apoptosis. This protective effect of Elmol and Dock180 is mediated by activation of Racl, p21-activated kinase (PAK) and AKT/protein kinase B (AKT) signaling. In zebrafish, Elmol and Dock 180 overexpression reduced the total apoptotic cell and apoptotic EC number and promoted the formation of blood vessels during embryogenesis. In conclusion, Elmol and Dock 180 protect ECs from apoptosis by the activation of the Rac 1/ PAK/AKT signaling cascade in vitro and in vivo. Thus, Elmol and Dock180 facilitate blood vessel formation by stabilization of the endothelium during angiogenesis.