ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice

Gastroenterology. 2010 Jan;138(1):360-371.e7. doi: 10.1053/j.gastro.2009.09.005. Epub 2009 Sep 18.


Background & aims: Severe polycystic liver disease can complicate adult dominant polycystic kidney disease, a genetic disease caused by defects in polycystin-1 (Pkd1) or polycystin-2 (Pkd2). Liver cyst epithelial cells (LCECs) express vascular endothelial growth factor (VEGF) and its receptor, VEGFR-2. We investigated the effects of VEGF on liver cyst growth and autocrine VEGF signaling in mice with Pkd1 and Pkd2 conditional knockouts.

Methods: We studied mice in which Pkd1 or Pkd2 were conditionally inactivated following exposure to tamoxifen; these mice were called Pkd1(flox/-):pCxCreER (Pkd1KO) and Pkd2(flox/-):pCxCreER (Pkd2KO).

Results: Pkd1KO and Pkd2KO mice developed liver defects; their LCECs expressed VEGF, VEGFR-2, hypoxia-inducible factor (HIF)-1alpha, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), and proliferating cell nuclear antigen (PCNA). In Pkd2KO but not Pkd1KO mice, exposure to the VEGFR-2 inhibitor SU5416 significantly reduced liver cyst development, liver/body weight ratio, and expression of pERK and PCNA. VEGF secretion and phosphorylation of ERK1/2 and VEGFR-2 were significantly increased in cultured LCECs from Pkd2KO compared with Pkd1KO mice. Inhibition of protein kinase A (PKA) reduced VEGF secretion and pERK1/2 expression. Addition of VEGF to LCECs from Pkd2KO mice increased phosphorylated VEGFR-2 and phosphorylated mitogen signal-regulated kinase (MEK) expression and induced phosphorylation of ERK1/2; this was inhibited by SU5416. Expression of HIF-1alpha increased in parallel with secretion of VEGF following LCEC stimulation. VEGF-induced cell proliferation was inhibited by the MEK inhibitor U1026 and by ERK1/2 small interfering RNA.

Conclusions: The PKA-ERK1/2-VEGF signaling pathway promotes growth of liver cysts in mice. In Pkd2-defective LCECs, PKA-dependent ERK1/2 signaling controls HIF-1alpha-dependent VEGF secretion and VEGFR-2 signaling. Autocrine and paracrine VEGF signaling promotes the growth of liver cysts in Pkd2KO mice. VEGF inhibitors might be used to treat patients with polycystic liver disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cysts / metabolism*
  • Cysts / pathology
  • Cysts / physiopathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Indoles / pharmacology
  • Liver Diseases / metabolism*
  • Liver Diseases / pathology
  • Liver Diseases / physiopathology
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phenotype
  • Phosphorylation / physiology
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Pyrroles / pharmacology
  • Repressor Proteins / metabolism
  • TRPP Cation Channels / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indoles
  • Proliferating Cell Nuclear Antigen
  • Protein Kinase Inhibitors
  • Pyrroles
  • Repressor Proteins
  • TRPP Cation Channels
  • Tip30 protein, mouse
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • polycystic kidney disease 1 protein
  • polycystic kidney disease 2 protein
  • vascular endothelial growth factor A, mouse
  • Semaxinib
  • Vascular Endothelial Growth Factor Receptor-2
  • Cyclic AMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3