Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide

J Clin Invest. 1995 Apr;95(4):1798-807. doi: 10.1172/JCI117858.


Endothelial cells constitute an essential integrator of factors that effect blood vessel remodeling induced by chronic hypoxia. We hypothesized that vascular endothelial growth factor (VEGF) may participate in the lung response to acute and to chronic hypoxia. We found that ex vivo perfusion of isolated lungs under hypoxic conditions (when compared with normoxia) caused an increase in lung tissue mRNA of VEGF and of the VEGF receptors KDR/Flk and Flt. Chronic hypobaric hypoxia also increased lung tissue mRNA levels of VEGF, KDR/Flk, and Flt and the amount of VEGF protein. In situ hybridization studies demonstrated increased VEGF and KDR/flk hybridization signals in lungs from chronically hypoxic rats. Since endotoxin treatment of rats decreased lung VEGF mRNA, we postulated that nitric oxide (NO) or an NO-related metabolite might be involved in lung VEGF gene expression. Indeed, sodium nitroprusside, a NO donor, decreased and L-NAME (N-nitro-L-arginine methyl ester), an inhibitor of NO-synthesis, increased both VEGF and VEGF receptor transcripts. We conclude that VEGF in the isolated perfused lung acts as an early gene in response to hypoxia and that lung VEGF and VEGF receptor mRNA levels are influenced by hypoxia and NO-dependent mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / biosynthesis
  • Actins / genetics
  • Animals
  • Arteries / pathology
  • Chronic Disease
  • Endothelial Growth Factors / biosynthesis*
  • Endothelial Growth Factors / genetics
  • Endotoxins / pharmacology
  • Gene Expression Regulation / drug effects
  • Glyceraldehyde-3-Phosphate Dehydrogenases / biosynthesis
  • Glyceraldehyde-3-Phosphate Dehydrogenases / genetics
  • Hypertrophy
  • Hypoxia / metabolism*
  • In Vitro Techniques
  • Lung / drug effects
  • Lung / metabolism*
  • Lung / pathology
  • Lymphokines / biosynthesis*
  • Lymphokines / genetics
  • Male
  • Nitric Oxide / pharmacology
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins / genetics
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / biosynthesis*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptors, Growth Factor / biosynthesis*
  • Receptors, Growth Factor / genetics
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factors


  • Actins
  • Endothelial Growth Factors
  • Endotoxins
  • Lymphokines
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Nitric Oxide
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-1