This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, S. Articles by Gerritsen, M. E. Search for Related Content PubMed PubMed Citation Articles by Yang, S. Articles by Gerritsen, M. E. Related Collections Health policy and outcome research Acute coronary syndromes

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1934.)
© 2001 American Heart Association, Inc.

Vascular Biology

Vascular Endothelial Cell Growth Factor-Driven Endothelial Tube Formation Is Mediated by Vascular Endothelial Cell Growth Factor Receptor-2, a Kinase Insert Domain-Containing Receptor

Suya Yang^*; Xiaohua Xin^*; Constance Zlot; Gladys Ingle; Germaine Fuh; Bing Li; Barbara Moffat; Abraham M. de Vos; Mary E. Gerritsen

From the Departments of Cardiovascular Research (S.Y., X.X., C.Z., G.I., M.E.G.) and Protein Engineering (G.F., B.L., B.M., A.M.d.V.), Genentech, Inc, South San Francisco, Calif.

Correspondence to Abraham M. de Vos, PhD, Department of Protein Engineering, Genentech, 1 DNA Wy, South San Francisco, CA 94080. E-mail devos{at}gene.com

Vascular endothelial cell growth factor (VEGF) binds to 2 related receptor tyrosine kinases, known as kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase (Flt-1). The KDR has been shown to mediate VEGF-stimulated endothelial cell mitogenesis, migration, and permeability. The Flt-1 receptor has been suggested to mediate VEGF-stimulated endothelial branching morphogenesis, a process whereby endothelial cells, in the presence of a 3D milieu composed of extracellular matrix components and a mixture of growth factors, undergo a morphological transition into a tubular network with many lumina. In the present study, we have used 2 independent endothelial cell tube formation models and highly selective VEGF mutants for the KDR and Flt-1 receptors. We demonstrate that KDR, not Flt-1, stimulation is responsible for the induction of endothelial tubulogenesis. In addition, we demonstrate a modulatory role for Flt-1 in VEGF-mediated tube formation. We also report that VEGF-driven endothelial tube formation is inhibited by selective inhibitors of mitogen-activated protein kinase activation and p38 protein kinase.

Key Words: angiogenesis • lumen • kinase insert domain-containing receptor • vascular endothelial cell growth factor • endothelium

This article has been cited by other articles:

				M. Korf-Klingebiel, T. Kempf, T. Sauer, E. Brinkmann, P. Fischer, G. P. Meyer, A. Ganser, H. Drexler, and K. C. Wollert Bone marrow cells are a rich source of growth factors and cytokines: implications for cell therapy trials after myocardial infarction Eur. Heart J., December 1, 2008; 29(23): 2851 - 2858. [Abstract] [Full Text] [PDF]

				W. Zheng, L. P. Christensen, and R. J. Tomanek Differential effects of cyclic and static stretch on coronary microvascular endothelial cell receptors and vasculogenic/angiogenic responses Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H794 - H800. [Abstract] [Full Text] [PDF]

				J.-i. Nishi, T. Minamino, H. Miyauchi, A. Nojima, K. Tateno, S. Okada, M. Orimo, J. Moriya, G.-H. Fong, K. Sunagawa, et al. Vascular Endothelial Growth Factor Receptor-1 Regulates Postnatal Angiogenesis Through Inhibition of the Excessive Activation of Akt Circ. Res., August 1, 2008; 103(3): 261 - 268. [Abstract] [Full Text] [PDF]

				M. Band, I. Shams, A. Joel, and A. Avivi Cloning and in vivo expression of vascular endothelial growth factor receptor 2 (Flk1) in the naturally hypoxia-tolerant subterranean mole rat FASEB J, January 1, 2008; 22(1): 105 - 112. [Abstract] [Full Text] [PDF]

				Y. Huang, X. Chen, M. M. Dikov, S. V. Novitskiy, C. A. Mosse, L. Yang, and D. P. Carbone Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF Blood, July 15, 2007; 110(2): 624 - 631. [Abstract] [Full Text] [PDF]

				P. Rocic, C. Kolz, R. Reed, B. Potter, and W. M. Chilian Optimal reactive oxygen species concentration and p38 MAP kinase are required for coronary collateral growth Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2729 - H2736. [Abstract] [Full Text] [PDF]

				S. Bohman, T. Matsumoto, K. Suh, A. Dimberg, L. Jakobsson, S. Yuspa, and L. Claesson-Welsh Proteomic Analysis of Vascular Endothelial Growth Factor-induced Endothelial Cell Differentiation Reveals a Role for Chloride Intracellular Channel 4 (CLIC4) in Tubular Morphogenesis J. Biol. Chem., December 23, 2005; 280(51): 42397 - 42404. [Abstract] [Full Text] [PDF]

				J. Woolard, W.-Y. Wang, H. S. Bevan, Y. Qiu, L. Morbidelli, R. O. Pritchard-Jones, T.-G. Cui, M. Sugiono, E. Waine, R. Perrin, et al. VEGF165b, an Inhibitory Vascular Endothelial Growth Factor Splice Variant: Mechanism of Action, In vivo Effect On Angiogenesis and Endogenous Protein Expression Cancer Res., November 1, 2004; 64(21): 7822 - 7835. [Abstract] [Full Text] [PDF]

				S. Kanda, Y. Miyata, and H. Kanetake Fibroblast Growth Factor-2-mediated Capillary Morphogenesis of Endothelial Cells Requires Signals via Flt-1/Vascular Endothelial Growth Factor Receptor-1: POSSIBLE INVOLVEMENT OF c-Akt J. Biol. Chem., February 6, 2004; 279(6): 4007 - 4016. [Abstract] [Full Text] [PDF]

				X. Gu, J. Zhang, D. W. Brann, and F.-S. X. Yu Brain and Retinal Vascular Endothelial Cells with Extended Life Span Established by Ectopic Expression of Telomerase Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 3219 - 3225. [Abstract] [Full Text] [PDF]

				S. Yang, K. Toy, G. Ingle, C. Zlot, P. M. Williams, G. Fuh, B. Li, A. de Vos, and M. E. Gerritsen Vascular Endothelial Growth Factor-Induced Genes in Human Umbilical Vein Endothelial Cells: Relative Roles of KDR and Flt-1 Receptors Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1797 - 1803. [Abstract] [Full Text] [PDF]