Janus face of vascular endothelial growth factor: the obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension

Crit Care Med. 2002 May;30(5 Suppl):S251-6. doi: 10.1097/00003246-200205001-00013.


Vascular endothelial growth factor (VEGF) plays a central role in the life and death of pulmonary vascular endothelial cells. Treatment of neonatal or adult rats with a VEGF receptor blocker destroys lung capillaries by inducing endothelial cell apoptosis and causes emphysema. Human lung tissue samples from patients with endstage emphysema have decreased levels of VEGF messenger RNA and protein and have decreased expression of kinase insert domain-containing receptor (VEGF receptor II). These decreases are associated with a high rate of alveolar septal cell apoptosis, indicating perhaps that decreased VEGF and kinase insert domain-containing receptor expression impairs endothelial cell survival in emphysematous lungs. Combination of VEGF receptor blockade with chronic hypoxia (3-wk exposure) results in obliteration of small precapillary pulmonary arteries by proliferating endothelial cells, severe pulmonary hypertension, and death caused by right-side heart failure. We propose that 1) VEGF receptor blockade causes endothelial cell apoptosis, 2) hypoxic vasoconstriction (shear stress) selects apoptosis-resistant endothelial cells that proliferate and obliterate the lumen, and 3) the vascular remodeling observed is relevant to the structural alterations that characterize severe pulmonary hypertension (including primary pulmonary hypertension) in humans. The endovascular cell growth in human disease and in our model exhibits some similarities with neoplastic cell growth. Chemotherapy strategies can now be employed in the animal model in an attempt to treat established vascular-obliterative lung disease.

Publication types

  • Review

MeSH terms

  • Animals
  • Apoptosis
  • Endothelial Growth Factors / physiology*
  • Endothelium, Vascular / physiology*
  • Endothelium, Vascular / ultrastructure
  • Humans
  • Hypertension, Pulmonary / etiology*
  • Lymphokines / physiology*
  • Phenotype
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / physiology
  • Receptors, Growth Factor / antagonists & inhibitors*
  • Receptors, Growth Factor / physiology
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Endothelial Growth Factors
  • Lymphokines
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor