Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 36; no. 4; pp. 655 - 662
• Main Authors: Castranova, Daniel, Davis, Andrew E, Lo, Brigid D, Miller, Mayumi F, Paukstelis, Paul J, Swift, Matthew R, Pham, Van N, Torres-Vázquez, Jesús, Bell, Kameha, Shaw, Kenna M, Kamei, Makoto, Weinstein, Brant M
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.04.2016
• Subjects: Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Activating Transcription Factor 6 - genetics; Activating Transcription Factor 6 - metabolism; Animals; Animals, Genetically Modified; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress; Gene Expression Regulation, Developmental; Genotype; Isoleucine-tRNA Ligase - deficiency; Isoleucine-tRNA Ligase - genetics; Mutation; Neovascularization, Physiologic; Phenotype; Regulatory Factor X Transcription Factors; Signal Transduction; Threonine-tRNA Ligase - deficiency; Threonine-tRNA Ligase - genetics; Transcription Factors - genetics; Transcription Factors - metabolism; Unfolded Protein Response; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; X-Box Binding Protein 1; Zebrafish; Zebrafish Proteins - deficiency; Zebrafish Proteins - genetics; protein kinases; unfolded protein response; zebrafish; vascular endothelial growth factor A; pathologic neovascularization; endoplasmic reticulum
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.115.307087

OBJECTIVE—Understanding the mechanisms regulating normal and pathological angiogenesis is of great scientific and clinical interest. In this report, we show that mutations in 2 different aminoacyl-transfer RNA synthetases, threonyl tRNA synthetase (tars) or isoleucyl tRNA synthetase (iars), lead to similar increased branching angiogenesis in developing zebrafish. APPROACH AND RESULTS—The unfolded protein response pathway is activated by aminoacyl-transfer RNA synthetase deficiencies, and we show that unfolded protein response genes atf4, atf6, and xbp1, as well as the key proangiogenic ligand vascular endothelial growth factor (vegfaa), are all upregulated in tars and iars mutants. Finally, we show that the protein kinase RNA-like endoplasmic reticulum kinase–activating transcription factor 4 arm of the unfolded protein response pathway is necessary for both the elevated vegfaa levels and increased angiogenesis observed in tars mutants. CONCLUSIONS—Our results suggest that endoplasmic reticulum stress acts as a proangiogenic signal via unfolded protein response pathway–dependent upregulation of vegfaa.