TY - JOUR
T1 - Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway
AU - Castranova, Daniel
AU - Davis, Andrew E.
AU - Lo, Brigid D.
AU - Miller, Mayumi F.
AU - Paukstelis, Paul J.
AU - Swift, Matthew R.
AU - Pham, Van N.
AU - Torres-Vázquez, Jesús
AU - Bell, Kameha
AU - Shaw, Kenna M.
AU - Kamei, Makoto
AU - Weinstein, Brant M.
N1 - Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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 (tarsy58) or isoleucyl tRNA synthetase (iarsy68), 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 tarsy58 and iarsy68 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 tarsy58 mutants. Conclusions - Our results suggest that endoplasmic reticulum stress acts as a proangiogenic signal via unfolded protein response pathway-dependent upregulation of vegfaa.
AB - 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 (tarsy58) or isoleucyl tRNA synthetase (iarsy68), 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 tarsy58 and iarsy68 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 tarsy58 mutants. Conclusions - Our results suggest that endoplasmic reticulum stress acts as a proangiogenic signal via unfolded protein response pathway-dependent upregulation of vegfaa.
KW - endoplasmic reticulum
KW - pathologic neovascularization
KW - protein kinases
KW - unfolded protein response
KW - vascular endothelial growth factor A
KW - zebrafish
UR - http://www.scopus.com/inward/record.url?scp=84955565769&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.115.307087
DO - 10.1161/ATVBAHA.115.307087
M3 - Article
C2 - 26821951
AN - SCOPUS:84955565769
SN - 1079-5642
VL - 36
SP - 655
EP - 662
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 4
ER -