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Hypoxia-induced endothelial progenitor cell function is blunted in angiotensinogen knockout mice.

Abstract
Angiotensinogen (AGT), the precursor of angiotensin I, is known to be involved in tumor angiogenesis and associated with the pathogenesis of coronary atherosclerosis. This study was undertaken to determine the role played by AGT in endothelial progenitor cells (EPCs) in tumor progression and metastasis. It was found that the number of EPC colonies formed by AGT heterozygous knockout (AGT(+/-)) cells was less than that formed by wild-type (WT) cells, and that the migration and tube formation abilities of AGT(+/-) EPCs were significantly lower than those of WT EPCs. In addition, the gene expressions of vascular endothelial growth factor (VEGF), Flk1, angiopoietin (Ang)-1, Ang-2, Tie-2, stromal derived factor (SDF)-1, C-X-C chemokine receptor type 4 (CXCR4), and of endothelial nitric oxide synthase (eNOS) were suppressed in AGT(+/-) EPCs. Furthermore, the expressions of hypoxia-inducible factor (HIF)-1α and -2α were downregulated in AGT(+/-) early EPCs under hypoxic conditions, suggesting a blunting of response to hypoxia. Moreover, the activation of Akt/eNOS signaling pathways induced by VEGF, epithelial growth factor (EGF), or SDF-1α were suppressed in AGT(+/-) EPCs. In AGT(+/-) mice, the incorporation of EPCs into the tumor vasculature was significantly reduced, and lung tumor growth and melanoma metastasis were attenuated. In conclusion, AGT is required for hypoxia-induced vasculogenesis.
AuthorsJin-Hwa Choi, Minh-Phuong Nguyen, Dongjin Lee, Goo-Taeg Oh, You-Mie Lee
JournalMolecules and cells (Mol Cells) Vol. 37 Issue 6 Pg. 487-96 (Jun 2014) ISSN: 0219-1032 [Electronic] Korea (South)
PMID24938229 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Agt protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Angiotensinogen
  • endothelial PAS domain-containing protein 1
Topics
  • Angiotensinogen (genetics, metabolism)
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
  • Cell Movement
  • Endothelial Progenitor Cells (metabolism, transplantation)
  • Gene Expression Regulation, Neoplastic
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
  • Lung Neoplasms (genetics, pathology, therapy)
  • Melanoma (pathology, secondary, therapy)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Transplantation
  • Signal Transduction

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