Intracellular pathways triggered by the selective FLT-1-agonist placental growth factor in vascular smooth muscle cells exposed to hypoxia

Br J Pharmacol. 2005 Oct;146(4):568-75. doi: 10.1038/sj.bjp.0706347.


We have previously shown that hypoxia makes vascular smooth muscle cells (VSMCs) responsive to placental growth factor (PlGF) through the induction of functional fms-like tyrosine kinase (Flt-1) receptors. The aim of this study was to investigate the molecular mechanisms involved in the PlGF effects on proliferation and contraction of VSMCs previously exposed to hypoxia (3% O2). In cultured rat VSMCs exposed to hypoxia, PlGF increased the phosphorylation of protein kinase B (Akt), p38 and STAT3; activation of STAT3 was higher than that of other kinases. In agreement with this finding, the proliferation of hypoxia-treated VSMCs in response to PlGF was significantly impaired by the p38 and the phosphatidylinositol 3-kinase inhibitors SB202190 and LY294002, respectively, and was almost completely prevented by AG490, a janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor. Since hypoxia was able to reverse the vasorelaxant effect of PlGF into a vasoconstrictor response, the mechanism of this latter effect was also investigated. Significant Flt-1 activity was measured in isolated preparations from rat aorta exposed to hypoxia. Inhibitors of mitogen-activated protein kinase kinase, Akt and STAT3 induced a modest inhibition of the vasoconstrictor response to PlGF, while the p38 inhibitor SB202190 markedly impaired the PlGF-induced contractile response. These effects were selectively mediated by Flt-1 without any involvement of foetal liver kinase-1 receptors. These data are the first evidence that different intracellular pathways activated by Flt-1 receptor in VSMCs are involved in diverse biological effects of PlGF: while mitogen activated protein kinase kinase/extracellular signal regulated kinase(1/2) and JAK/STAT play a role in VSMC proliferation, p38 is involved in VSMC contraction. These findings may highlight the role of PlGF in vascular pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / cytology
  • Aorta, Thoracic / drug effects*
  • Aorta, Thoracic / metabolism
  • Cell Hypoxia
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chromones / pharmacology
  • Dose-Response Relationship, Drug
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Male
  • Morpholines / pharmacology
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Placenta Growth Factor
  • Pregnancy Proteins / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Time Factors
  • Tyrphostins / pharmacology
  • Vascular Endothelial Growth Factor Receptor-1 / drug effects*
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • Vasoconstriction / drug effects
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Chromones
  • Imidazoles
  • Morpholines
  • Pgf protein, rat
  • Phosphoinositide-3 Kinase Inhibitors
  • Pregnancy Proteins
  • Pyridines
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Placenta Growth Factor
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Flt1 protein, rat
  • Vascular Endothelial Growth Factor Receptor-1
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole