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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 microg.kg(-1).day(-1)) augmented while low-dose mini-TyrRS (3 microg.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.

Original publication

DOI

10.1152/ajpregu.90519.2008

Type

Journal article

Journal

Am J Physiol Regul Integr Comp Physiol

Publication Date

10/2008

Volume

295

Pages

R1138 - R1146

Keywords

Animals, Aorta, Thoracic, Arteries, Capillaries, Capillary Permeability, Cattle, Cell Movement, Ear, External, Femoral Artery, Humans, Hypoxia, Ischemia, Leukocytes, Ligation, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Muscle, Skeletal, Neovascularization, Physiologic, Peptide Fragments, Rats, Regional Blood Flow, Tyrosine-tRNA Ligase, Vascular Endothelial Growth Factor A, Vasoconstriction