Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin

Am J Pathol. 1996 Jul;149(1):293-305.


We have identified several mechanisms by which the angiogenic cytokine vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) likely regulates endothelial cells (EC) migration. VPF/VEGF induced dermal microvascular EC expression of mRNAs encoding the alphav and beta3 integrin subunits resulting in increased levels of the alphavbeta3 heterodimer at the cell surface, and VPF/VEGF also induced mRNA encoding osteopontin (OPN), an alphavbeta3 ligand. OPN promoted EC migration in vitro; and VPF/VEGF induction of alphavbeta3 was accompanied by increased EC migration toward OPN. Because thrombin cleavage of OPN results in substantial enhancement of OPN's adhesive properties, and because VPF/VEGF promotes increased microvascular permeability leading to activation of the extrinsic coagulation pathway, we also investigated whether VPF/VEGF facilitates thrombin cleavage of OPN in vivo. Consistent with this hypothesis, co-injection of VPF/VEGF together with OPN resulted in rapid cleavage of OPN by endogenous thrombin. Furthermore, in comparison with native OPN, thrombin-cleaved OPN stimulated a greater rate of EC migration in vitro, which was additive to the increased migration associated with induction of alpha v beta 3. Thus, these data demonstrate cooperative mechanisms for VPF/VEGF regulation of EC migration involving the alphavbeta3 integrin, the alphavbeta3 ligand OPN, and thrombin cleavage of OPN. These findings also illustrate an operational link between VPF/VEGF induction of EC gene expression and VPF/VEGF enhancement of microvascular permeability, suggesting that these distinct biological activities may act accordingly to stimulate EC migration during angiogenesis.

Publication types

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

MeSH terms

  • Animals
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Cells, Cultured
  • Endothelial Growth Factors / pharmacology
  • Endothelial Growth Factors / physiology*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology*
  • Female
  • Guinea Pigs
  • Humans
  • Infant, Newborn
  • Integrins / physiology*
  • Lymphokines / pharmacology
  • Lymphokines / physiology*
  • Male
  • Osteopontin
  • RNA, Messenger / analysis
  • RNA, Messenger / drug effects
  • Receptors, Vitronectin / physiology*
  • Sialoglycoproteins / pharmacology
  • Sialoglycoproteins / physiology*
  • Thrombin / physiology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Endothelial Growth Factors
  • Integrins
  • Lymphokines
  • RNA, Messenger
  • Receptors, Vitronectin
  • SPP1 protein, human
  • Sialoglycoproteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Osteopontin
  • Thrombin