This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, D. Articles by Cavenee, W. K. Search for Related Content PubMed PubMed Citation Articles by Wang, D. Articles by Cavenee, W. K.

Induction of Vascular Endothelial Growth Factor Expression in Endothelial Cells by Platelet-derived Growth Factor through the Activation of Phosphatidylinositol 3-Kinase

Ludwig Institute for Cancer Research [D. W., H-J. S. H., W. K. C.], Department of Medicine [H-J. S. H., W. K. C.], Center for Molecular Genetics [W. K. C.], and Cancer Center [W. K. C.], University of California-San Diego, California 92093-0660, and Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114 [A. K.]

Increased numbers of platelet-derived growth factor ß receptors (ßPDGFRs) on neovascular endothelial cells is a common occurrence in several pathological conditions including wound healing, inflammation, and glioma tumorigenesis. Here we sought to test the biological significance of this by determining whether expression of wild-type ßPDGFR by normal aortic endothelial cells affected the expression of the vascular endothelial growth factor (VEGF), a critical angiogenesis regulator and mitogen for such cells. The results showed that PDGF could increase transcription and secretion of VEGF by ßPDGFR-expressing endothelial cells. Moreover, we further demonstrated a requirement for the activation of phosphatidylinositol 3-kinase (PI3K) in this response by using chemical inhibitors of PI3K, mutant PDGFR, and dominant-negative PI3K. These studies suggest a novel mechanism by which PDGF induces VEGF expression in endothelial cells, define VEGF as a downstream target for PI3K, and invoke a role for PI3K in angiogenesis.

This article has been cited by other articles:

				R. J. Tomanek, H. K. Hansen, and L. P. Christensen Temporally Expressed PDGF and FGF-2 Regulate Embryonic Coronary Artery Formation and Growth Arterioscler. Thromb. Vasc. Biol., July 1, 2008; 28(7): 1237 - 1243. [Abstract] [Full Text] [PDF]

				S. de Bouard, P. Herlin, J. G. Christensen, E. Lemoisson, P. Gauduchon, E. Raymond, and J.-S. Guillamo Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma Neuro-oncol, October 1, 2007; 9(4): 412 - 423. [Abstract] [Full Text] [PDF]

				K. Cho, T. Ishiwata, E. Uchida, N. Nakazawa, M. Korc, Z. Naito, and T. Tajiri Enhanced Expression of Keratinocyte Growth Factor and Its Receptor Correlates with Venous Invasion in Pancreatic Cancer Am. J. Pathol., June 1, 2007; 170(6): 1964 - 1974. [Abstract] [Full Text] [PDF]

				I. F. Pollack, R. I. Jakacki, S. M. Blaney, M. L. Hancock, M. W. Kieran, P. Phillips, L. E. Kun, H. Friedman, R. Packer, A. Banerjee, et al. Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: A Pediatric Brain Tumor Consortium report Neuro-oncol, April 1, 2007; 9(2): 145 - 160. [Abstract] [Full Text] [PDF]

				A. Ponten, E. Bergsten Folestad, K. Pietras, and U. Eriksson Platelet-Derived Growth Factor D Induces Cardiac Fibrosis and Proliferation of Vascular Smooth Muscle Cells in Heart-Specific Transgenic Mice Circ. Res., November 11, 2005; 97(10): 1036 - 1045. [Abstract] [Full Text] [PDF]

				E. B. Dickerson, R. Thomas, S. P. Fosmire, A. R. Lamerato-Kozicki, S. R. Bianco, J. W. Wojcieszyn, M. Breen, S. C. Helfand, and J. F. Modiano Mutations of Phosphatase and Tensin Homolog Deleted from Chromosome 10 in Canine Hemangiosarcoma Vet. Pathol., September 1, 2005; 42(5): 618 - 632. [Abstract] [Full Text] [PDF]

				L. Xu, R. Tong, D. M. Cochran, and R. K. Jain Blocking Platelet-Derived Growth Factor-D/Platelet-Derived Growth Factor Receptor {beta} Signaling Inhibits Human Renal Cell Carcinoma Progression in an Orthotopic Mouse Model Cancer Res., July 1, 2005; 65(13): 5711 - 5719. [Abstract] [Full Text] [PDF]

				N. Ouchi, R. Shibata, and K. Walsh AMP-Activated Protein Kinase Signaling Stimulates VEGF Expression and Angiogenesis in Skeletal Muscle Circ. Res., April 29, 2005; 96(8): 838 - 846. [Abstract] [Full Text] [PDF]

				S. Basciani, M. Brama, S. Mariani, G. De Luca, M. Arizzi, L. Vesci, C. Pisano, S. Dolci, G. Spera, and L. Gnessi Imatinib Mesylate Inhibits Leydig Cell Tumor Growth: Evidence for In vitro and In vivo Activity Cancer Res., March 1, 2005; 65(5): 1897 - 1903. [Abstract] [Full Text] [PDF]

				W. G. Roberts, P. M. Whalen, E. Soderstrom, G. Moraski, J. P. Lyssikatos, H.-F. Wang, B. Cooper, D. A. Baker, D. Savage, D. Dalvie, et al. Antiangiogenic and Antitumor Activity of a Selective PDGFR Tyrosine Kinase Inhibitor, CP-673,451 Cancer Res., February 1, 2005; 65(3): 957 - 966. [Abstract] [Full Text] [PDF]

				X. Deng, S. Szabo, T. Khomenko, M. R. Jadus, and M. Yoshida Gene Therapy with Adenoviral Plasmids or Naked DNA of Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor Accelerates Healing of Duodenal Ulcer in Rats J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 982 - 988. [Abstract] [Full Text] [PDF]

				Y. Wu, Q. Zhang, D. K. Ann, A. Akhondzadeh, H. S. Duong, D. V. Messadi, and A. D. Le Increased vascular endothelial growth factor may account for elevated level of plasminogen activator inhibitor-1 via activating ERK1/2 in keloid fibroblasts Am J Physiol Cell Physiol, April 1, 2004; 286(4): C905 - C912. [Abstract] [Full Text] [PDF]

				C. Saucier, H. Khoury, K.-M. V. Lai, P. Peschard, D. Dankort, M. A. Naujokas, J. Holash, G. D. Yancopoulos, W. J. Muller, T. Pawson, et al. The Shc adaptor protein is critical for VEGF induction by Met/HGF and ErbB2 receptors and for early onset of tumor angiogenesis PNAS, February 24, 2004; 101(8): 2345 - 2350. [Abstract] [Full Text] [PDF]

				G. Boguslawski, P. W. McGlynn, K. A. Harvey, and A. T. Kovala SU1498, an Inhibitor of Vascular Endothelial Growth Factor Receptor 2, Causes Accumulation of Phosphorylated ERK Kinases and Inhibits Their Activity in Vivo and in Vitro J. Biol. Chem., February 13, 2004; 279(7): 5716 - 5724. [Abstract] [Full Text] [PDF]

				D. J. Brat and T. B. Mapstone Malignant Glioma Physiology: Cellular Response to Hypoxia and Its Role in Tumor Progression Ann Intern Med, April 15, 2003; 138(8): 659 - 668. [Full Text] [PDF]

				P. Guo, B. Hu, W. Gu, L. Xu, D. Wang, H.-J. S. Huang, W. K. Cavenee, and S.-Y. Cheng Platelet-Derived Growth Factor-B Enhances Glioma Angiogenesis by Stimulating Vascular Endothelial Growth Factor Expression in Tumor Endothelia and by Promoting Pericyte Recruitment Am. J. Pathol., April 1, 2003; 162(4): 1083 - 1093. [Abstract] [Full Text] [PDF]

				S. Kiriakidis, E. Andreakos, C. Monaco, B. Foxwell, M. Feldmann, and E. Paleolog VEGF expression in human macrophages is NF-{kappa}B-dependent: studies using adenoviruses expressing the endogenous NF-{kappa}B inhibitor I{kappa}B{alpha} and a kinase-defective form of the I{kappa}B kinase 2 J. Cell Sci., February 15, 2003; 116(4): 665 - 674. [Abstract] [Full Text] [PDF]

				N. Pore, S. Liu, D. A. Haas-Kogan, D. M. O'Rourke, and A. Maity PTEN Mutation and Epidermal Growth Factor Receptor Activation Regulate Vascular Endothelial Growth Factor (VEGF) mRNA Expression in Human Glioblastoma Cells by Transactivating the Proximal VEGF Promoter Cancer Res., January 1, 2003; 63(1): 236 - 241. [Abstract] [Full Text] [PDF]

				S. A. Woods, C. J. McGlade, and A. Guha Phosphatidylinositol 3'-kinase and MAPK/ERK kinase 1/2 differentially regulate expression of vascular endothelial growth factor in human malignant astrocytoma cells Neuro-oncol, October 1, 2002; 4(4): 242 - 252. [Abstract] [PDF]

				C. Treins, S. Giorgetti-Peraldi, J. Murdaca, G. L. Semenza, and E. Van Obberghen Insulin Stimulates Hypoxia-inducible Factor 1 through a Phosphatidylinositol 3-Kinase/Target of Rapamycin-dependent Signaling Pathway J. Biol. Chem., July 26, 2002; 277(31): 27975 - 27981. [Abstract] [Full Text] [PDF]

				C. B. Knobbe, A. Merlo, and G. Reifenberger Pten signaling in gliomas Neuro-oncol, July 1, 2002; 4(3): 196 - 211. [Abstract] [PDF]

				L. J. Metheny-Barlow, B. Flynn, H. E. van Gijssel, A. Marrogi, and B. I. Gerwin Paradoxical Effects of Platelet-Derived Growth Factor-A Overexpression in Malignant Mesothelioma . Antiproliferative Effects In Vitro and Tumorigenic Stimulation In Vivo Am. J. Respir. Cell Mol. Biol., June 1, 2001; 24(6): 694 - 702. [Abstract] [Full Text] [PDF]

				E. Y. Chen, N. M. Mazure, J. A. Cooper, and A. J. Giaccia Hypoxia Activates a Platelet-derived Growth Factor Receptor/Phosphatidylinositol 3-Kinase/Akt Pathway That Results in Glycogen Synthase Kinase-3 Inactivation Cancer Res., March 1, 2001; 61(6): 2429 - 2433. [Abstract] [Full Text]

				B. D. Smolich, H. A. Yuen, K. A. West, F. J. Giles, M. Albitar, and J. M. Cherrington The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts Blood, March 1, 2001; 97(5): 1413 - 1421. [Abstract] [Full Text] [PDF]

				S. Xiong, R. Grijalva, L. Zhang, N. T. Nguyen, P. W. Pisters, R. E. Pollock, and D. Yu Up-Regulation of Vascular Endothelial Growth Factor in Breast Cancer Cells by the Heregulin-{beta}1-activated p38 Signaling Pathway Enhances Endothelial Cell Migration Cancer Res., February 1, 2001; 61(4): 1727 - 1732. [Abstract] [Full Text]

				A. Maity, N. Pore, J. Lee, D. Solomon, and D. M. O’Rourke Epidermal Growth Factor Receptor Transcriptionally Up-Regulates Vascular Endothelial Growth Factor Expression in Human Glioblastoma Cells via a Pathway Involving Phosphatidylinositol 3'-Kinase and Distinct from That Induced by Hypoxia Cancer Res., October 1, 2000; 60(20): 5879 - 5886. [Abstract] [Full Text]

				W. Zundel, C. Schindler, D. Haas-Kogan, A. Koong, F. Kaper, E. Chen, A. R. Gottschalk, H. E. Ryan, R. S. Johnson, A. B. Jefferson, et al. Loss of PTEN facilitates HIF-1-mediated gene expression Genes & Dev., February 15, 2000; 14(4): 391 - 396. [Abstract] [Full Text]

				R. Bagheri-Yarmand, R. K. Vadlamudi, R.-A. Wang, J. Mendelsohn, and R. Kumar Vascular Endothelial Growth Factor Up-regulation via p21-activated Kinase-1 Signaling Regulates Heregulin-beta 1-mediated Angiogenesis J. Biol. Chem., December 8, 2000; 275(50): 39451 - 39457. [Abstract] [Full Text] [PDF]

				B.-H. Jiang, J. Z. Zheng, M. Aoki, and P. K. Vogt Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells PNAS, February 15, 2000; 97(4): 1749 - 1753. [Abstract] [Full Text] [PDF]