Published online before print January 20, 2005, doi: 10.1161/01.RES.0000156273.30274.f7
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© 2005 American Heart Association, Inc.
Molecular Medicine |
Glycogen-Synthase Kinase3ß/ß-Catenin Axis Promotes Angiogenesis Through Activation of Vascular Endothelial Growth Factor Signaling in Endothelial Cells
From the Whitaker Cardiovascular Institute (C.S., H.M., E.R., A.B., K.W.), Boston University Medical Center, Boston, Mass; and the Department of Medicine (T.F.), Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Mass.
Correspondence to Kenneth Walsh, PhD, Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany St, W611, Boston, MA 02118. E-mail kxwalsh{at}bu.edu
Glycogen-Synthase Kinase 3ß (GSK3ß) has been shown to function as a nodal point of converging signaling pathways in endothelial cells to regulate vessel growth, but the signaling mechanisms downstream from GSK3ß have not been identified. Here, we show that ß-catenin is an important downstream target for GSK3ß action in angiogenesis and dissect the signal transduction pathways involved in the angiogenic phenotype. Transduction of human umbilical vein endothelial cells (HUVECs) with a kinase-mutant form of the enzyme (KM-GSK3ß) increased cytosolic ß-catenin levels, whereas constitutively active GSK3ß (S9A-GSK3ß) reduced ß-catenin levels. Lymphoid enhancer factor/T-cell factor promoter activity was upregulated by KM-GSK3ß and diminished by S9A-GSK3ß, whereas manipulation of Akt signaling had no effect on this parameter. ß-Catenin transduction induced capillary formation in a Matrigel-plug assay in vivo and promoted endothelial cell differentiation into network structures on Matrigel-coated plates in vitro. ß-Catenin activated the expression of vascular endothelial growth factor (VEGF)-A and VEGF-C in endothelial cells, and these effects were mediated at the levels of protein, mRNA, and promoter activity. Consistent with these data, ß-catenin increased the phosphorylation of the VEGF receptor 2 (VEGF-R2) and promoted its association with PI3-kinase, leading to a dose-dependent activation of the serine–threonine kinase Akt. Inhibition of PI3-kinase or Akt signaling led to a significant reduction in the pro-angiogenic activity of ß-catenin. Collectively, these data show that the growth factor–PI3-kinase–Akt axis functions downstream of GSK3ß/ß-catenin signaling in endothelial cells to promote angiogenesis.
Key Words: ß-catenin • Akt • endothelial cells • vacular endothelial growth factor • VEGF receptor 2 • angiogenesis
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