Tie2 Receptor Ligands, Angiopoietin-1 and Angiopoietin-2, Modulate VEGF-Induced Postnatal Neovascularization

From the Departments of Medicine (Cardiology) and Biomedical Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass; and Regeneron Pharmaceuticals, Inc (G.D.Y.), Tarrytown, NY.

Correspondence to Jeffrey M. Isner, MD, St. Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135.

Abstract—Angiopoietin-1 (Ang1) has been recently identified as the major physiological ligand for the tyrosine kinase receptor Tie2 and assigned responsibility for recruiting and sustaining periendothelial support cells. Angiopoietin-2 (Ang2) was found to disrupt blood vessel formation in the developing embryo by antagonizing the effects of Ang1 and Tie2 and was thus considered to represent a natural Ang1/Tie2 inhibitor. In vivo effects of either angiopoietin on postnatal neovascularization, however, have not been previously described. Accordingly, we used the cornea micropocket assay of neovascularization to investigate the impact of angiopoietins on neovascularization in vivo. Neither Ang1 nor Ang2 alone promoted neovascularization. Pellets containing vascular endothelial growth factor (VEGF) alone induced corneal neovascularity extending from the limbus across the cornea. Addition of Ang1 to VEGF (Ang1+VEGF) produced an increase in macroscopically evident perfusion of the corneal neovasculature without affecting macroscopic measurements of length (0.58±0.03 mm) or circumferential neovascularity (136±10°). In contrast, pellets containing Ang2+VEGF promoted significantly longer (0.67±0.05 mm) and more circumferential (160±15°) neovascularity than VEGF alone or Ang1+VEGF (P<0.05). Excess soluble Tie2 receptor (sTie2-Fc) precluded modulation of VEGF-induced neovascularization by both Ang2 and Ang1. Fluorescent microscopic findings demonstrated enhanced capillary density (fluorescence intensity, 2.55±0.23 e⁺⁹ versus 1.23±0.17 e⁺⁹, P<0.01) and increased luminal diameter of the basal limbus artery (39.0±2.8 versus 27.9±1.3 µm, P<0.01) for Ang1+VEGF compared with VEGF alone. In contrast to Ang1+VEGF, Ang2+VEGF produced longer vessels and, at the tip of the developing capillaries, frequent isolated sprouting cells. In the case of Ang2+VEGF, however, luminal diameter of the basal limbus artery was not increased (26.7±1.9 versus 27.9±1.3, P=NS). These findings constitute what is to our knowledge the first direct demonstration of postnatal bioactivity associated with either angiopoietin. In particular, these results indicate that angiopoietins may potentiate the effects of other angiogenic cytokines. Moreover, these findings provide in vivo evidence that Ang1 promotes vascular network maturation, whereas Ang2 works to initiate neovascularization.

Key Words: angiopoietin • Tie2 receptor • vascular endothelial growth factor • angiogenesis • endothelial cell

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				C.-H. Cho, R. A. Kammerer, H. J. Lee, M. O. Steinmetz, Y. S. Ryu, S. H. Lee, K. Yasunaga, K.-T. Kim, I. Kim, H.-H. Choi, et al. COMP-Ang1: A designed angiopoietin-1 variant with nonleaky angiogenic activity PNAS, April 13, 2004; 101(15): 5547 - 5552. [Abstract] [Full Text] [PDF]

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				P. Pichiule, J. C. Chavez, and J. C. LaManna Hypoxic Regulation of Angiopoietin-2 Expression in Endothelial Cells J. Biol. Chem., March 26, 2004; 279(13): 12171 - 12180. [Abstract] [Full Text] [PDF]

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				D.C Felmeden, A.D Blann, and G.Y.H Lip Angiogenesis: basic pathophysiology and implications for disease Eur. Heart J., April 1, 2003; 24(7): 586 - 603. [Full Text] [PDF]

				A. I. Nykanen, R. Krebs, A. Saaristo, P. Turunen, K. Alitalo, S. Yla-Herttuala, P. K. Koskinen, and K. B. Lemstrom Angiopoietin-1 Protects Against the Development of Cardiac Allograft Arteriosclerosis Circulation, March 11, 2003; 107(9): 1308 - 1314. [Abstract] [Full Text] [PDF]

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				Y. Yamada, Y. Oike, H. Ogawa, Y. Ito, H. Fujisawa, T. Suda, and N. Takakura Neuropilin-1 on hematopoietic cells as a source of vascular development Blood, March 1, 2003; 101(5): 1801 - 1809. [Abstract] [Full Text] [PDF]

				H. Takagi, S. Koyama, H. Seike, H. Oh, A. Otani, M. Matsumura, and Y. Honda Potential Role of the Angiopoietin/Tie2 System in Ischemia-Induced Retinal Neovascularization Invest. Ophthalmol. Vis. Sci., January 1, 2003; 44(1): 393 - 402. [Abstract] [Full Text] [PDF]

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				W.-H. Zhu, A. MacIntyre, and R. F. Nicosia Regulation of Angiogenesis by Vascular Endothelial Growth Factor and Angiopoietin-1 in the Rat Aorta Model : Distinct Temporal Patterns of Intracellular Signaling Correlate with Induction of Angiogenic Sprouting Am. J. Pathol., September 1, 2002; 161(3): 823 - 830. [Abstract] [Full Text] [PDF]

				E. S. J. M. de Bont, V. Fidler, T. Meeuwsen, F. Scherpen, K. Hahlen, and W. A. Kamps Vascular Endothelial Growth Factor Secretion Is an Independent Prognostic Factor for Relapse-free Survival in Pediatric Acute Myeloid Leukemia Patients Clin. Cancer Res., September 1, 2002; 8(9): 2856 - 2861. [Abstract] [Full Text] [PDF]

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				E. Tham, J. Wang, F. Piehl, and G. Weber Upregulation of VEGF-A Without Angiogenesis in a Mouse Model of Dilated Cardiomyopathy Caused by Mitochondrial Dysfunction J. Histochem. Cytochem., July 1, 2002; 50(7): 935 - 944. [Abstract] [Full Text] [PDF]

				S.-C. Shih, G. S. Robinson, C. A. Perruzzi, A. Calvo, K. Desai, J. E. Green, I. U. Ali, L. E. H. Smith, and D. R. Senger Molecular Profiling of Angiogenesis Markers Am. J. Pathol., July 1, 2002; 161(1): 35 - 41. [Abstract] [Full Text] [PDF]

				G. Camenisch, M. T. Pisabarro, D. Sherman, J. Kowalski, M. Nagel, P. Hass, M.-H. Xie, A. Gurney, S. Bodary, X. H. Liang, et al. ANGPTL3 Stimulates Endothelial Cell Adhesion and Migration via Integrin alpha vbeta 3 and Induces Blood Vessel Formation in Vivo J. Biol. Chem., May 3, 2002; 277(19): 17281 - 17290. [Abstract] [Full Text] [PDF]

				K. Rodins, M. Cheale, N. Coleman, and S. B. Fox Minichromosome Maintenance Protein 2 Expression in Normal Kidney and Renal Cell Carcinomas: Relationship to Tumor Dormancy and Potential Clinical Utility Clin. Cancer Res., April 1, 2002; 8(4): 1075 - 1081. [Abstract] [Full Text] [PDF]

				S.M. DALLABRIDA and M.A. RUPNICK Vascular Endothelium in Tissue Remodeling: Implications for Heart Failure Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 417 - 428. [Abstract] [PDF]

				K.S. MOULTON Plaque Angiogenesis: Its Functions and Regulation Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 471 - 482. [Abstract] [PDF]

				K. J. Sales, A. A. Katz, B. Howard, R. P. Soeters, R. P. Millar, and H. N. Jabbour Cyclooxygenase-1 Is Up-Regulated in Cervical Carcinomas: Autocrine/Paracrine Regulation of Cyclooxygenase-2, Prostaglandin E Receptors, and Angiogenic Factors by Cyclooxygenase-1 Cancer Res., January 1, 2002; 62(2): 424 - 432. [Abstract] [Full Text] [PDF]

				S. B. Freedman and J. M. Isner Therapeutic Angiogenesis for Coronary Artery Disease Ann Intern Med, January 1, 2002; 136(1): 54 - 71. [Abstract] [Full Text] [PDF]

				E. S. J. M. de Bont, J. E. J. Guikema, F. Scherpen, T. Meeuwsen, W. A. Kamps, E. Vellenga, and N. A. Bos Mobilized Human CD34+ Hematopoietic Stem Cells Enhance Tumor Growth in a Nonobese Diabetic/Severe Combined Immunodeficient Mouse Model of Human Non-Hodgkin's Lymphoma Cancer Res., October 1, 2001; 61(20): 7654 - 7659. [Abstract] [Full Text] [PDF]

				K. Koga, T. Todaka, M. Morioka, J.-i. Hamada, Y. Kai, S. Yano, A. Okamura, N. Takakura, T. Suda, and Y. Ushio Expression of Angiopoietin-2 in Human Glioma Cells and Its Role for Angiogenesis Cancer Res., August 1, 2001; 61(16): 6248 - 6254. [Abstract] [Full Text] [PDF]

				A. L. Harris, P. Reusch, B. Barleon, C. Hang, N. Dobbs, and D. Marme Soluble Tie2 and Flt1 Extracellular Domains in Serum of Patients with Renal Cancer and Response to Antiangiogenic Therapy Clin. Cancer Res., July 1, 2001; 7(7): 1992 - 1997. [Abstract] [Full Text] [PDF]

				M. Yokoyama and T. Hirase Harmonic Interplay of Angiogenic Growth Factors in the Development of Coronary Blood Vessels Circ. Res., June 8, 2001; 88(11): 1099 - 1101. [Full Text] [PDF]

				R Tabibiazar and S.G Rockson Angiogenesis and the ischaemic heart Eur. Heart J., June 1, 2001; 22(11): 903 - 918. [PDF]

				M. Hangai, T. Murata, N. Miyawaki, C. Spee, J. I. Lim, S. He, D. R. Hinton, and S. J. Ryan Angiopoietin-1 Upregulation by Vascular Endothelial Growth Factor in Human Retinal Pigment Epithelial Cells Invest. Ophthalmol. Vis. Sci., June 1, 2001; 42(7): 1617 - 1625. [Abstract] [Full Text]

				A. Otani, H. Takagi, H. Oh, S. Koyama, and Y. Honda Angiotensin II Induces Expression of the Tie2 Receptor Ligand, Angiopoietin-2, in Bovine Retinal Endothelial Cells Diabetes, April 1, 2001; 50(4): 867 - 875. [Abstract] [Full Text]

				M. J. Currie, S. P. Gunningham, C. Han, P. A. E. Scott, B. A. Robinson, A. L. Harris, and S. B. Fox Angiopoietin-1 Is Inversely Related to Thymidine Phosphorylase Expression in Human Breast Cancer, Indicating a Role in Vascular Remodeling Clin. Cancer Res., April 1, 2001; 7(4): 918 - 927. [Abstract] [Full Text]

				K. Teichert-Kuliszewska, P. C. Maisonpierre, N. Jones, A. I.M. Campbell, Z. Master, M. P. Bendeck, K. Alitalo, D. J. Dumont, G. D. Yancopoulos, and D. J. Stewart Biological action of angiopoietin-2 in a fibrin matrix model of angiogenesis is associated with activation of Tie2 Cardiovasc Res, February 16, 2001; 49(3): 659 - 670. [Abstract] [Full Text] [PDF]

				S. A. Ahmad, W. Liu, Y. D. Jung, F. Fan, M. Wilson, N. Reinmuth, R. M. Shaheen, C. D. Bucana, and L. M. Ellis The Effects of Angiopoietin-1 and -2 on Tumor Growth and Angiogenesis in Human Colon Cancer Cancer Res., February 1, 2001; 61(4): 1255 - 1259. [Abstract] [Full Text]

				S. Fujiyama, H. Matsubara, Y. Nozawa, K. Maruyama, Y. Mori, Y. Tsutsumi, H. Masaki, Y. Uchiyama, Y. Koyama, A. Nose, et al. Angiotensin AT1 and AT2 Receptors Differentially Regulate Angiopoietin-2 and Vascular Endothelial Growth Factor Expression and Angiogenesis by Modulating Heparin Binding-Epidermal Growth Factor (EGF)-Mediated EGF Receptor Transactivation Circ. Res., January 19, 2001; 88(1): 22 - 29. [Abstract] [Full Text] [PDF]

				J. K. Chae, I. Kim, S. T. Lim, M. J. Chung, W. H. Kim, H. G. Kim, J. K. Ko, and G. Y. Koh Coadministration of Angiopoietin-1 and Vascular Endothelial Growth Factor Enhances Collateral Vascularization Arterioscler Thromb Vasc Biol, December 1, 2000; 20(12): 2573 - 2578. [Abstract] [Full Text] [PDF]

				C. Wulff, H. Wilson, P. Largue, W. C. Duncan, D. G. Armstrong, and H. M. Fraser Angiogenesis in the Human Corpus Luteum: Localization and Changes in Angiopoietins, Tie-2, and Vascular Endothelial Growth Factor Messenger Ribonucleic Acid J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4302 - 4309. [Abstract] [Full Text]

				C. Willam, P. Koehne, J. S. Jurgensen, M. Grafe, K. D. Wagner, S. Bachmann, U. Frei, and K.-U. Eckardt Tie2 Receptor Expression Is Stimulated by Hypoxia and Proinflammatory Cytokines in Human Endothelial Cells Circ. Res., September 1, 2000; 87(5): 370 - 377. [Abstract] [Full Text] [PDF]

				T. Uchida, M. Nakashima, Y. Hirota, Y. Miyazaki, T. Tsukazaki, and H. Shindo Immunohistochemical localisation of protein tyrosine kinase receptors Tie-1 and Tie-2 in synovial tissue of rheumatoid arthritis: correlation with angiogenesis and synovial proliferation Ann Rheum Dis, August 1, 2000; 59(8): 607 - 614. [Abstract] [Full Text]

				M. Bongrazio, C. Baumann, A. Zakrzewicz, A. R Pries, and P. Gaehtgens Evidence for modulation of genes involved in vascular adaptation by prolonged exposure of endothelial cells to shear stress Cardiovasc Res, August 1, 2000; 47(2): 384 - 393. [Abstract] [Full Text] [PDF]