Advertisement
GET OUR E-ALERTS
Research Articles

Angiopoietin-2, a Natural Antagonist for Tie2 That Disrupts in vivo Angiogenesis

Peter C. Maisonpierre, Chitra Suri, Pamela F. Jones, Sona Bartunkova, Stanley J. Wiegand, Czeslaw Radziejewski, Debra Compton, Joyce McClain, Thomas H. Aldrich, Nick Papadopoulos, Thomas J. Daly, Samuel Davis, Thomas N. Sato, and George D. Yancopoulos
Science
4 Jul 1997
Vol 277, Issue 5322
pp. 55-60
DOI: 10.1126/science.277.5322.55
get access

Abstract

Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell–specific Tie2 receptor tyrosine kinase. Like vascular endothelial growth factor, Ang1 is essential for normal vascular development in the mouse. An Ang1 relative, termed angiopoietin-2 (Ang2), was identified by homology screening and shown to be a naturally occurring antagonist for Ang1 and Tie2. Transgenic overexpression of Ang2 disrupts blood vessel formation in the mouse embryo. In adult mice and humans, Ang2 is expressed only at sites of vascular remodeling. Natural antagonists for vertebrate receptor tyrosine kinases are atypical; thus, the discovery of a negative regulator acting on Tie2 emphasizes the need for exquisite regulation of this angiogenic receptor system.

Get full access to this article

View all available purchase options and get full access to this article.

Get Access
Already a subscriber or AAAS Member?

REFERENCES AND NOTES

1
Risau W., FASEB J. 9, 926 (1995);
; Nature 386, 671 (1997).
2
Folkman J., Nature Med. 1, 27 (1995).
3
Hanahan D., Folkman J., Cell 86, 353 (1996).
4
Mustonen T., Alitalo K., J. Cell Biol. 129, 895 (1995).
5
Fong G. H., Rossant J., Gertenstein M., Breitman M. L., Nature 376, 66 (1995);
; F. Shalaby et al., ibid., p. 62; P. Carmeliet et al., ibid.380, 435 (1996); N. Ferrara et al., ibid., p. 439.
6
Jackson D., Volpert O. V., Bouck N., Linzer D. I. H., Science 266, 1581 (1994).
7
M. S. O'Reilly et al., Cell 79, 315 (1994).
8
M. S. O'Reilly et al., ibid.88, 277 (1997).
9
Davis S., et al., ibid. 87, 1161 (1996).
10
Dumont D. J., Yamaguchi T. P., Conlon R. A., Rossant J., Breitman M. L., Oncogene 7, 1471 (1992);
Maisonpierre P. C., Goldfarb M., Yancopoulos G. D., Gao G., ibid. 8, 1631 (1993);
Sato T. N., Qin Y., Kozak C. A., Audus K. L., Proc. Natl. Acad. Sci. U.S.A. 90, 9355 (1993);
Schnurch H., Risau W., Development 119, 957 (1993);
Ziegler S. F., Bird T. A., Schneringer K. A., Schooley K. A., Baum P. R., Oncogene 8, 663 (1993).
11
A. Iwama et al., Biochem. Biophys. Res. Commun.195, 301 (1993).
12
Dumont D. J., et al., Genes Dev. 8, 1897 (1994);
Sato T. N., et al., Nature 376, 70 (1995).
13
Suri C., et al., Cell 87, 1171 (1996).
14
Cloning of Ang2 cDNAs resulted from screening a human fetal lung and a mouse adult uterus cDNA library (both from Clontech) with the full-length mouse 32P-labeled Ang1 cDNA probe at 55° or 65°C (25).
15
Mutation of Cys245 in Ang1, which is not shared between Ang1 and Ang2, does not alter its agonistic properties. For some experiments, Ang1* (a recombinant version of Ang1 with a modified NH2-terminus and mutated Cys245 that is easier to produce and purify) was used instead of Ang1; for details on expression and purification of Ang1, Ang1*, and Ang2, see S. Davis et al., in preparation.
16
Partanen J., et al., Mol. Cell. Biol. 12, 1698 (1992).
17
P. C. Maisonpierre et al., data not shown.
18
K. K. Hirschi and P. A. D'Amore, Cardiovasc. Res.32, 687 (1996).
19
Findlay J. K., J. Endocrinol. 111, 357 (1986);
Phillips H. S., Hains J., Leung D. W., Ferrara N., Endocrinology 127, 965 (1990);
Shweiki D., Itin A., Neufeld G., Gitay-Goren H., Keshet E., J. Clin. Invest. 91, 2235 (1993);
Bacharach E., Itin A., Keshet E., Proc. Natl. Acad. Sci. U.S.A. 89, 10686 (1992).
20
Schlaeger T. M., et al., Proc. Natl. Acad. Sci. U.S.A. 94, 3058 (1997).
21
Schweitzer R., Howes R., Smith R., Shilo B.-Z., Freeman M., Nature 376, 699 (1995).
22
Cioce V., et al., J. Biol. Chem. 271, 13110 (1996).
23
Arend W. P., Welgus H. G., Thompson R. C., Eisenberg S. P., J. Clin. Invest. 85, 1694 (1990).
24
Vikkula M., et al., Cell 87, 1181 (1996).
25
Maisonpierre P. C., et al., Science 247, 1446 (1990).
26
Edgell C.-J. S., McDonald C. C., Graham J. B., Proc. Natl. Acad. Sci. U.S.A. 80, 3734 (1983).
27
P. C. Maisonpierre, P. F. Jones, S. Davis, G. D. Yancopoulos, in preparation.
28
Probes for mouse embryo sections were 560- and 680-nucleotide (nt) cRNAs extending from 5′ leader sequence to, respectively, codon 165 in mouse Ang1 cDNA and codon 155 in mouse Ang2 cDNA. Probes for rat ovary sections were VEGF, a 141-nt cRNA spanning the last 47 rat VEGF codons (which are shared among most VEGF RNA splice-variants); Ang1, a 773-nt cRNA spanning the last 257 codons of mouse Ang1 cDNA; and Ang2, a 315-nt cRNA spanning codons 380 to 485 in rat Ang2 cDNA.
29
To obtain staged ovulating ovarian tissue, we injected immature (postnatal day 29) female Sprague-Dawley rats (Zivic-Miller) with 5 U of pregnant mare serum gonadotropin (Calbiochem). Rats were killed and ovaries were surgically removed beginning at 56 hours after injection and at 9- to 32-hour intervals thereafter.
30
We thank L. S. Schleifer and P. R. Vagelos for enthusiastic support; M. Goldfarb, M. Wang, R. Rossman, D. Datta, Y. Qing, T. Schlaeger, J. Lawitts, and J. Bruno for their contributions; J. Springhorn for HUCEC cells; and C. Murphy, E. Hubel, C. Rudowsky, and E. Burrows for graphics work. T.N.S. was partly supported by Hoffmann–LaRoche Inc.

Information & Authors

Information

Published In

Science
Volume 277 | Issue 5322
4 July 1997

Submission history

Received: 7 March 1997
Accepted: 13 May 1997
Published in print: 4 July 1997

Permissions

Request permissions for this article.

Authors

Affiliations

Peter C. Maisonpierre*
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Chitra Suri*
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Pamela F. Jones*,†
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Sona Bartunkova*
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Stanley J. Wiegand
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Czeslaw Radziejewski
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Debra Compton
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Joyce McClain
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Thomas H. Aldrich
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Nick Papadopoulos
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Thomas J. Daly
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Samuel Davis*
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
Thomas N. Sato*
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author
George D. Yancopoulos*,‡
P. C. Maisonpierre, C. Suri, P. F. Jones, S. J. Wiegand, C. Radziejewski, D. Compton, J. McClain, T. H. Aldrich, N. Papadopoulos, T. J. Daly, S. Davis, and G. D. Yancopoulos are at Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. S. Bartunkova and T. N. Sato are at Beth Israel–Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
View all articles by this author

Notes

*
These authors contributed equally to this article.
†
Present address: Molecular Medicine, St. James University Hospital, Leeds LS9 7TS, UK.
‡
To whom correspondence should be addressed. E-mail: [email protected]

Metrics & Citations

Metrics

Article Usage

Note: The article usage is presented with a three- to four-day delay and will update daily once available. Due to this delay, usage data will not appear immediately following publication.

Citation information is sourced from Crossref Cited-by service.

Altmetrics

Citations

Export citation

Select the format you want to export the citation of this publication.

Cited by

    • Zaipul I. Md Dom,
    • Eiichiro Satake,
    • Jan Skupien,
    • Bozena Krolewski,
    • Kristina O’Neil,
    • Jill A. Willency,
    • Simon T. Dillon,
    • Jonathan M. Wilson,
    • Hiroki Kobayashi,
    • Katsuhito Ihara,
    • Towia A. Libermann,
    • Marlon Pragnell,
    • Kevin L. Duffin,
    • Andrzej S. Krolewski,
    Circulating proteins protect against renal decline and progression to end-stage renal disease in patients with diabetes, Science Translational Medicine, 13, 600, (2021)./doi/10.1126/scitranslmed.abd2699
    Abstract
    • Veli-Matti Leppänen,
    • Pascal Brouillard,
    • Emilia A. Korhonen,
    • Tuomas Sipilä,
    • Sawan Kumar Jha,
    • Nicole Revencu,
    • Veerle Labarque,
    • Elodie Fastré,
    • Matthieu Schlögel,
    • Marie Ravoet,
    • Amihood Singer,
    • Claudia Luzzatto,
    • Donatella Angelone,
    • Giovanni Crichiutti,
    • Angela D’Elia,
    • Jaakko Kuurne,
    • Harri Elamaa,
    • Gou Young Koh,
    • Pipsa Saharinen,
    • Miikka Vikkula,
    • Kari Alitalo,
    Characterization of ANGPT2 mutations associated with primary lymphedema, Science Translational Medicine, 12, 560, (2021)./doi/10.1126/scitranslmed.aax8013
    Abstract
    • Sarah J. Higgins,
    • Lisa A. Purcell,
    • Karlee L. Silver,
    • Vanessa Tran,
    • Valerie Crowley,
    • Michael Hawkes,
    • Andrea L. Conroy,
    • Robert O. Opoka,
    • John G. Hay,
    • Susan E. Quaggin,
    • Gavin Thurston,
    • W. Conrad Liles,
    • Kevin C. Kain,
    Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria, Science Translational Medicine, 8, 358, (358ra128-358ra128), (2021)./doi/10.1126/scitranslmed.aaf6812
    Abstract
    • Kari Alitalo,
    • Annalisa M. VanHook,
    Science Signaling Podcast: 2 July 2013, Science Signaling, 6, 282, (pc16-pc16), (2021)./doi/10.1126/scisignal.2004435
    Abstract
    • Dongeun Huh,
    • Daniel C. Leslie,
    • Benjamin D. Matthews,
    • Jacob P. Fraser,
    • Samuel Jurek,
    • Geraldine A. Hamilton,
    • Kevin S. Thorneloe,
    • Michael Allen McAlexander,
    • Donald E. Ingber,
    A Human Disease Model of Drug Toxicity–Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice, Science Translational Medicine, 4, 159, (159ra147-159ra147), (2021)./doi/10.1126/scitranslmed.3004249
    Abstract
    • Yihai Cao,
    • Jack Arbiser,
    • Robert J. D’Amato,
    • Patricia A. D’Amore,
    • Donald E. Ingber,
    • Robert Kerbel,
    • Michael Klagsbrun,
    • Sharon Lim,
    • Marsha A. Moses,
    • Bruce Zetter,
    • Harold Dvorak,
    • Robert Langer,
    Forty-Year Journey of Angiogenesis Translational Research, Science Translational Medicine, 3, 114, (114rv3-114rv3), (2021)./doi/10.1126/scitranslmed.3003149
    Abstract
    • Dean Y. Li,
    • Lise K. Sorensen,
    • Benjamin S. Brooke,
    • Lisa D. Urness,
    • Elaine C. Davis,
    • Douglas G. Taylor,
    • Beth B. Boak,
    • Daniel P. Wendel,
    Defective Angiogenesis in Mice Lacking Endoglin, Science, 284, 5419, (1534-1537), (2021)./doi/10.1126/science.284.5419.1534
    Abstract
    • J. Holash,
    • P. C. Maisonpierre,
    • D. Compton,
    • P. Boland,
    • C. R. Alexander,
    • D. Zagzag,
    • G. D. Yancopoulos,
    • S. J. Wiegand,
    Vessel Cooption, Regression, and Growth in Tumors Mediated by Angiopoietins and VEGF, Science, 284, 5422, (1994-1998), (2021)./doi/10.1126/science.284.5422.1994
    Abstract
    • Douglas Hanahan,
    Signaling Vascular Morphogenesis and Maintenance, Science, 277, 5322, (48-50), (2021)./doi/10.1126/science.277.5322.48
    Abstract
    • Chitra Suri,
    • Joyce McClain,
    • Gavin Thurston,
    • Donald M. McDonald,
    • Hao Zhou,
    • Eben H. Oldmixon,
    • Thomas N. Sato,
    • George D. Yancopoulos,
    Increased Vascularization in Mice Overexpressing Angiopoietin-1, Science, 282, 5388, (468-471), (1998)./doi/10.1126/science.282.5388.468
    Abstract

Citation information is sourced from Crossref Cited-by service.

View Options

Get Access

Log in to view the full text

AAAS ID LOGIN

AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.

Log in via OpenAthens.
via OpenAthens
Log in via Shibboleth.
via Shibboleth
More options

Purchase digital access to this article

Download and print this article for your personal scholarly, research, and educational use.

Purchase this issue in print

Buy a single issue of Science for just $15 USD.

View options

PDF format

Download this article as a PDF file

Download PDF

Media

Figures

Multimedia

Tables

Share

Share

Share article link

Share on social media

Current Issue

Go to Science
Table of Contents

LATEST NEWS