Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension

FASEB J. 2001 Feb;15(2):427-38. doi: 10.1096/fj.00-0343com.


Our understanding of the pathobiology of severe pulmonary hypertension, usually a fatal disease, has been hampered by the lack of information of its natural history. We have demonstrated that, in human severe pulmonary hypertension, the precapillary pulmonary arteries show occlusion by proliferated endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR-2) are involved in proper maintenance, differentiation, and function of endothelial cells. We demonstrate here that VEGFR-2 blockade with SU5416 in combination with chronic hypobaric hypoxia causes severe pulmonary hypertension associated with precapillary arterial occlusion by proliferating endothelial cells. Prior to and concomitant with the development of severe pulmonary hypertension, lungs of chronically hypoxic SU5416-treated rats show significant pulmonary endothelial cell death, as demonstrated by activated caspase 3 immunostaining and TUNEL. The broad caspase inhibitor Z-Asp-CH2-DCB prevents the development of intravascular pulmonary endothelial cell growth and severe pulmonary hypertension caused by the combination of SU5416 and chronic hypoxia.

Publication types

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

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Apoptosis / drug effects*
  • Blood Pressure / drug effects
  • Caspase 3
  • Caspases / analysis
  • Cell Death / drug effects
  • Cell Division / drug effects
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Heart Ventricles
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology*
  • Hypoxia / physiopathology*
  • Indoles / pharmacology*
  • Male
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / physiopathology
  • Myocardium / pathology
  • Pulmonary Artery / drug effects*
  • Pulmonary Artery / pathology
  • Pulmonary Artery / physiopathology
  • Pyrroles / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptors, Growth Factor / antagonists & inhibitors*
  • Receptors, Vascular Endothelial Growth Factor


  • Angiogenesis Inhibitors
  • Indoles
  • Pyrroles
  • Receptors, Growth Factor
  • Semaxinib
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • CASP3 protein, human
  • Casp3 protein, rat
  • Caspase 3
  • Caspases