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Science 24 December 1999:
Vol. 286. no. 5449, pp. 2511 - 2514
DOI: 10.1126/science.286.5449.2511
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Reports

Leakage-Resistant Blood Vessels in Mice Transgenically Overexpressing Angiopoietin-1

G. Thurston, 1* C. Suri, 2 K. Smith, 1 J. McClain, 2 T. N. Sato, 3 G. D. Yancopoulos, 2* D. M. McDonald 1

Angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF) are endothelial cell-specific growth factors. Direct comparison of transgenic mice overexpressing these factors in the skin revealed that the VEGF-induced blood vessels were leaky, whereas those induced by Ang1 were nonleaky. Moreover, vessels in Ang1-overexpressing mice were resistant to leaks caused by inflammatory agents. Coexpression of Ang1 and VEGF had an additive effect on angiogenesis but resulted in leakage-resistant vessels typical of Ang1. Ang1 therefore may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated VEGF and, in combination with VEGF, for promoting growth of nonleaky vessels.

1 Department of Anatomy and Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0452, USA.
2 Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
3 University of Texas, Southwestern Medical Center, Dallas, TX 75235, USA.
*   To whom correspondence should be addressed. E-mail: gavint{at}itsa.ucsf.edu or gdy{at}regpha.com

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Altered Levels of Angiopoietin 1 and Tie 2 Are Associated with Androgen-Regulated Vascular Regression and Growth in the Ventral Prostate in Adult Mice and Rats.
A. Johansson, S. H. Rudolfsson, P. Wikstrom, and A. Bergh (2005)
Endocrinology 146, 3463-3470
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Activation of hypoxia-inducible factors in hyperoxia through prolyl 4-hydroxylase blockade in cells and explants of primate lung.
T. M. Asikainen, B. K. Schneider, N. S. Waleh, R. I. Clyman, W.-B. Ho, L. A. Flippin, V. Gunzler, and C. W. White (2005)
PNAS 102, 10212-10217
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Angiopoietin 1 causes vessel enlargement, without angiogenic sprouting, during a critical developmental period.
G. Thurston, Q. Wang, F. Baffert, J. Rudge, N. Papadopoulos, D. Jean-Guillaume, S. Wiegand, G. D. Yancopoulos, and D. M. McDonald (2005)
Development 132, 3317-3326
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Targeted Deletion of Fgl-2/Fibroleukin in the Donor Modulates Immunologic Response and Acute Vascular Rejection in Cardiac Xenografts.
M. Mendicino, M. Liu, A. Ghanekar, W. He, C. Koscik, I. Shalev, M. Javadi, J. Turnbull, W. Chen, L. Fung, et al. (2005)
Circulation 112, 248-256
   Abstract »    Full Text »    PDF »
Long-Term and Sustained COMP-Ang1 Induces Long-Lasting Vascular Enlargement and Enhanced Blood Flow.
C.-H. Cho, K. E. Kim, J. Byun, H.-S. Jang, D.-K. Kim, P. Baluk, F. Baffert, G. M. Lee, N. Mochizuki, J. Kim, et al. (2005)
Circ. Res. 97, 86-94
   Abstract »    Full Text »    PDF »
Angiopoietin-1 Opposes VEGF-Induced Increase in Endothelial Permeability by Inhibiting TRPC1-Dependent Ca2 Influx.
D. Jho, D. Mehta, G. Ahmmed, X.-P. Gao, C. Tiruppathi, M. Broman, and A. B. Malik (2005)
Circ. Res. 96, 1282-1290
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Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation.
T. Morisada, Y. Oike, Y. Yamada, T. Urano, M. Akao, Y. Kubota, H. Maekawa, Y. Kimura, M. Ohmura, T. Miyamoto, et al. (2005)
Blood 105, 4649-4656
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Effects of Protein and Gene Transfer of the Angiopoietin-1 Fibrinogen-like Receptor-binding Domain on Endothelial and Vessel Organization.
C. C. Weber, H. Cai, M. Ehrbar, H. Kubota, G. Martiny-Baron, W. Weber, V. Djonov, E. Weber, A. S. Mallik, M. Fussenegger, et al. (2005)
J. Biol. Chem. 280, 22445-22453
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Selective Role of a Distinct Tyrosine Residue on Tie2 in Heart Development and Early Hematopoiesis.
K. Tachibana, N. Jones, D. J. Dumont, M. C. Puri, and A. Bernstein (2005)
Mol. Cell. Biol. 25, 4693-4702
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Local Delivery of Angiopoietin-2 into the Preovulatory Follicle Terminates the Menstrual Cycle in Rhesus Monkeys.
F. Xu and R. L. Stouffer (2005)
Biol Reprod 72, 1352-1358
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Oligomerization and Multimerization Are Critical for Angiopoietin-1 to Bind and Phosphorylate Tie2.
K.-T. Kim, H.-H. Choi, M. O. Steinmetz, B. Maco, R. A. Kammerer, S. Y. Ahn, H.-Z. Kim, G. M. Lee, and G. Y. Koh (2005)
J. Biol. Chem. 280, 20126-20131
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Functional Ephrin-B2 Expression for Promotive Interaction Between Arterial and Venous Vessels in Postnatal Neovascularization.
S.-i. Hayashi, T. Asahara, H. Masuda, J. M. Isner, and D. W. Losordo (2005)
Circulation 111, 2210-2218
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Angiopoietin concentrations in diabetic retinopathy.
J I Patel, P G Hykin, Z J Gregor, M Boulton, and I A Cree (2005)
Br J Ophthalmol 89, 480-483
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Hematopoietic cells regulate the angiogenic switch during tumorigenesis.
R. Okamoto, M. Ueno, Y. Yamada, N. Takahashi, H. Sano, T. Suda, and N. Takakura (2005)
Blood 105, 2757-2763
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Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter.
M. Sugaya, T. Watanabe, A. Yang, M. F. Starost, H. Kobayashi, A. M. Atkins, D. L. Borris, E. A. Hanan, D. Schimel, M. A. Bryant, et al. (2005)
Blood 105, 2356-2363
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Reappraisal of Recent Clinical Trials of Angiogenic Therapy in Myocardial Ischemia.
C. J Teng, K. Lachapelle, and R. C. Chiu (2005)
Asian Cardiovasc Thorac Ann 13, 90-97
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