Abstract
Engulfment and cell motility 1/dedicator of cytokinesis 180 (Elmo1/Dock180) is a bipartite guanine nucleotide exchange factor for the monomeric GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1). Elmo1/Dock180 regulates Rac1 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 Elmo1/Dock180 regulates endothelial function and vascular development remained elusive. In this study, we aimed to analyze the vascular function of Elmo1 and Dock180 in human ECs and during vascular development in zebrafish embryos. In vitro overexpression of Elmo1 and Dock180 in ECs reduced caspase-3/7 activity and annexin V-positive cell number upon induction of apoptosis. This protective effect of Elmo1 and Dock180 is mediated by activation of Rac1, p21-activated kinase (PAK) and AKT/protein kinase B (AKT) signaling. In zebrafish, Elmo1 and Dock180 overexpression reduced the total apoptotic cell and apoptotic EC number and promoted the formation of blood vessels during embryogenesis. In conclusion, Elmo1 and Dock180 protect ECs from apoptosis by the activation of the Rac1/PAK/AKT signaling cascade in vitro and in vivo. Thus, Elmo1 and Dock180 facilitate blood vessel formation by stabilization of the endothelium during angiogenesis.
Highlights
The endothelium requires stabilization factors for efficient blood vessel formation
In this study we have identified a novel protective function for the related C3 botulinum toxin substrate 1 (Rac1) activator Elmo1/Dock180 in the endothelium, which is mediated by PAK1, phosphoinositide 3-kinase (PI3K), and AKT/protein kinase B (AKT) (Fig. 6)
In zebrafish embryos, Elmo1 and Dock180 overexpression reduced the number of apoptotic endothelial cells (ECs) after apoptosis induction and rescued vascular malformation
Summary
The endothelium requires stabilization factors for efficient blood vessel formation. Results: Engulfment and cell motility 1/dedicator of cytokinesis 180 (Elmo1/Dock180) expression reduces endothelial cell apoptosis in vitro and in vivo. Conclusion: Elmo1/Dock180 protects endothelial cells from apoptosis and acts as a stabilization factor for the endothelium. Elmo1/Dock180 regulates Rac 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. In vitro overexpression of Elmo and Dock180 in ECs reduced caspase-3/7 activity and annexin V-positive cell number upon induction of apoptosis. This protective effect of Elmo and Dock180 is mediated by activation of Rac, p21-activated kinase (PAK) and AKT/protein kinase B (AKT) signaling. Elmo and Dock180 overexpression reduced the total apoptotic cell and apoptotic EC number and promoted the formation of blood vessels during embryogenesis. Elmo and Dock180 protect ECs from apoptosis by the activation of the Rac1/PAK/AKT signaling cascade in vitro and in vivo. Elmo and Dock180 facilitate blood vessel formation by stabilization of the endothelium during angiogenesis
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