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

Daniel Castranova1, Andrew E Davis1, Brigid D Lo1

  • 1From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).

Arteriosclerosis, Thrombosis, and Vascular Biology
|January 30, 2016
PubMed
Abstract

Insights

Mutations in aminoacyl-transfer RNA synthetases cause increased blood vessel formation (angiogenesis) in zebrafish by activating the unfolded protein response pathway and upregulating vascular endothelial growth factor.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • Angiogenesis, the formation of new blood vessels, is crucial for development and disease.
  • Understanding the molecular regulators of angiogenesis is vital for therapeutic interventions.

Purpose of the Study:

  • To investigate the role of aminoacyl-transfer RNA synthetases in angiogenesis.
  • To elucidate the molecular mechanisms linking these enzymes to blood vessel formation.

Main Methods:

  • Utilized zebrafish (Danio rerio) as a model organism.
  • Generated and analyzed mutations in threonyl tRNA synthetase (tars) and isoleucyl tRNA synthetase (iars) genes.
  • Assessed angiogenesis, unfolded protein response (UPR) gene expression, and vascular endothelial growth factor (VEGF) levels.

Main Results:

  • Mutations in tars and iars led to significantly increased angiogenesis in zebrafish.
  • Aminoacyl-transfer RNA synthetase deficiencies activated the UPR pathway, upregulating UPR genes (atf4, atf6, xbp1).
  • Vascular endothelial growth factor A (vegfaa) was upregulated in mutants, and the activating transcription factor 4 (ATF4) arm of the UPR was essential for elevated vegfaa and angiogenesis.

Conclusions:

  • Endoplasmic reticulum (ER) stress, triggered by aminoacyl-transfer RNA synthetase dysfunction, acts as a proangiogenic signal.
  • The UPR pathway mediates this effect through the upregulation of vegfaa.
  • These findings reveal a novel link between protein synthesis machinery and angiogenic signaling.
Keywords:
endoplasmic reticulumpathologic neovascularizationprotein kinasesunfolded protein responsevascular endothelial growth factor Azebrafish

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