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Am J Physiol Regul Integr Comp Physiol 295: R1138-R1146, 2008. First published August 27, 2008; doi:10.1152/ajpregu.90519.2008
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HEMODYNAMICS AND CARDIORENAL INTEGRATION

Effect of mini-tyrosyl-tRNA synthetase on ischemic angiogenesis, leukocyte recruitment, and vascular permeability

Gang Cheng,1 Hua Zhang,1 Xianglei Yang,2 Eleni Tzima,1 Karla L. Ewalt,3 Paul Schimmel,2 and James E. Faber1

1Department of Cell and Molecular Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 2Department of Molecular Biology, The Scripps Research Institute, La Jolla, California; and 3aTyr Pharma, San Diego, California

Submitted 19 June 2008 ; accepted in final form 14 August 2008

Mini-tyrosyl-tRNA synthetase (mini-TyrRS), the N-terminal domain of tyrosyl-tRNA synthetase, is a recently identified protein released by endothelial cells that exhibits angiogenic and leukocyte chemoattractant, ELR-motif (Glu-Leu-Arg)-dependent activities in vitro. We sought to determine whether exogenous mini-TyrRS exerts these and other cytokine-like actions in physiological and pathological settings in vivo. High-dose mini-TyrRS (600 µg·kg–1·day–1) augmented while low-dose mini-TyrRS (3 µg·kg–1·day–1), unexpectedly, inhibited angiogenesis in the ischemic mouse ear. Enhanced angiogenesis was associated with increased CD45- and CD4-positive leukocyte accumulation. Mini-TyrRS also had biphasic actions on both basal and mustard oil-evoked and VEGF-evoked leakage of Evan's blue dye-albumin in nonischemic ear and in endothelial cell monolayers, that is, low-dose inhibited and high-dose augmented leakage. Mutation of the ELR motif of mini-TyrRS abolished the above activities. Mini-TyrRS was reduced (immunoblot) in extracts of ischemic calf muscle and in thoracic aorta explants exposed to hypoxia or VEGF. Inhibition of VEGF with a soluble Flt1 "trap" protein abolished this hypoxic-induced reduction in mini-TyrRS in aorta explants. These data show that mini-TyrRS has dose-dependent biphasic effects on ischemic angiogenesis and vascular permeability in vivo, that is, antiangiogenic and antipermeability activities at low concentration and proangiogenic, propermeability activities at high concentrations.

hypoxia; ischemia; vascular endothelial growth factor


Address for reprint requests and other correspondence: J. E. Faber, Dept. of Cell and Molecular Physiology, 6309 MBRB, Univ. of North Carolina, Chapel Hill, NC 27599-7545 (e-mail: jefaber{at}med.unc.edu)






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