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

Abstract

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 y58 ) or isoleucyl tRNA synthetase (iars y68 ) , 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 y58 and iars y68 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 y58 mutants. Conclusions— Our results suggest that endoplasmic reticulum stress acts as a proangiogenic signal via unfolded protein response pathway–dependent upregulation of vegfaa.