Differential activation of vascular genes by hypoxia in primary endothelial cells

Exp Cell Res. 2004 Oct 1;299(2):476-85. doi: 10.1016/j.yexcr.2004.06.005.


Changes in the local environment, such as reduced oxygen tension (hypoxia), elicit transcriptional activation of a variety of genes in mammalian cells. Here we have analyzed the effect of hypoxia in different vascular endothelial cells (ECs) with emphasis on hypoxia-regulated transcription factors and genes of importance for blood vessel dynamics. While hypoxia induced the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) in all endothelial cells tested, the closely related HIF-2alpha protein was markedly induced in microvascular/capillary endothelial cells, but only weakly or not at all in artery and vein endothelial cells. Furthermore, microvascular/capillary endothelial cells responded to hypoxia with increased number of transcripts encoding vascular endothelial growth factor-A (VEGF-A), VEGF receptor-2, the angiopoietin receptor Tie2, platelet-derived growth factor-B (PDGF-B), and inducible nitric oxide synthase (iNOS). In vein endothelial cells, hypoxia instead increased transcripts encoding lymphatic vascular components VEGF-C, -D, and VEGF receptor-3. Finally, reduced VEGF receptor levels and phosphorylation indicated establishment of a functional autocrine VEGF-A loop in hypoxic endothelial cells. Our results show that endothelial cells, derived from different vascular beds, mount different transcriptional responses to changes in oxygen tension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Becaplermin
  • Blood Vessels / cytology
  • Blood Vessels / metabolism
  • Cattle
  • Cell Hypoxia*
  • Electrophoretic Mobility Shift Assay
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Infant, Newborn
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Platelet-Derived Growth Factor / metabolism
  • Proto-Oncogene Proteins c-sis
  • Pulmonary Artery / cytology
  • Pulmonary Artery / metabolism
  • Receptor, TIE-2 / metabolism
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Skin / cytology
  • Skin / metabolism
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Umbilical Veins / cytology
  • Umbilical Veins / metabolism
  • Vascular Endothelial Growth Factor A / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Trans-Activators
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • endothelial PAS domain-containing protein 1
  • Becaplermin
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Receptor, TIE-2
  • Receptors, Vascular Endothelial Growth Factor