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Science 30 October 1998:
Vol. 282. no. 5390, pp. 946 - 949
DOI: 10.1126/science.282.5390.946
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Reports

Cardiovascular Failure in Mouse Embryos Deficient in VEGF Receptor-3

Daniel J. Dumont, *dagger Lotta Jussila, * Jussi Taipale, * Athina Lymboussaki, Tuija Mustonen, Katri Pajusola, Martin Breitman, ddagger Kari Alitalo §

Vascular endothelial growth factor (VEGF) is a key regulator of blood vessel development in embryos and angiogenesis in adult tissues. Unlike VEGF, the related VEGF-C stimulates the growth of lymphatic vessels through its specific lymphatic endothelial receptor VEGFR-3. Here it is shown that targeted inactivation of the gene encoding VEGFR-3 resulted in defective blood vessel development in early mouse embryos. Vasculogenesis and angiogenesis occurred, but large vessels became abnormally organized with defective lumens, leading to fluid accumulation in the pericardial cavity and cardiovascular failure at embryonic day 9.5. Thus, VEGFR-3 has an essential role in the development of the embryonic cardiovascular system before the emergence of the lymphatic vessels.

D. J. Dumont, Ontario Cancer Institute and Amgen Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1. L. Jussila, J. Taipale, A. Lymboussaki, T. Mustonen, K. Pajusola, K. Alitalo, Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, PL 21 (Haartmaninkatu 3), 00014 Helsinki, Finland. M. Breitman, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
*   These authors contributed equally to this work.

dagger    Present address: Sunnybrook Health Science Centre, Division of Cancer Biology, S Wing Research Building, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.

ddagger    Deceased.

§   To whom correspondence should be addressed. E-mail: Kari.Alitalo{at}Helsinki.FI

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Vascular Endothelial Growth Factor-D Expression Is an Independent Prognostic Marker for Survival in Colorectal Carcinoma.
J. D. White, P. W. Hewett, D. Kosuge, T. McCulloch, B. C. Enholm, J. Carmichael, and J. C. Murray (2002)
Cancer Res. 62, 1669-1675
   Abstract »    Full Text »    PDF »
Molecular Mechanisms of Lymphangiogenesis.
T. MAKINEN and K. ALITALO (2002)
Cold Spring Harb Symp Quant Biol 67, 189-196
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Vascular Endothelial Growth Factor (VEGF) Receptor-2 Antagonists Inhibit VEGF- and Basic Fibroblast Growth Factor-Induced Angiogenesis in Vivo and in Vitro.
J.-C. Tille, J. Wood, S.J. Mandriota, C. Schnell, S. Ferrari, J. Mestan, Z. Zhu, L. Witte, and M. S. Pepper (2001)
J. Pharmacol. Exp. Ther. 299, 1073-1085
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Stimulation of beta 1 Integrin Induces Tyrosine Phosphorylation of Vascular Endothelial Growth Factor Receptor-3 and Modulates Cell Migration.
J. F. Wang, X.-F. Zhang, and J. E. Groopman (2001)
J. Biol. Chem. 276, 41950-41957
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor Signaling Pathway as an Emerging Target in Hematologic Malignancies.
A. F. List (2001)
Oncologist 6, 24-31
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A recurrent deletion in the ubiquitously expressed NEMO (IKK-{gamma}) gene accounts for the vast majority of incontinentia pigmenti mutations.
S. Aradhya, H. Woffendin, T. Jakins, T. Bardaro, T. Esposito, A. Smahi, C. Shaw, M. Levy, A. Munnich, M. D'Urso, et al. (2001)
Hum. Mol. Genet. 10, 2171-2179
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Stromal cells expressing ephrin-B2 promote the growth and sprouting of ephrin-B2+ endothelial cells.
X.-Q. Zhang, N. Takakura, Y. Oike, T. Inada, N. W. Gale, G. D. Yancopoulos, and T. Suda (2001)
Blood 98, 1028-1037
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Vascular Endothelial Growth Factor-B-Deficient Mice Display an Atrial Conduction Defect.
K. Aase, G. von Euler, X. Li, A. Ponten, P. Thoren, R. Cao, Y. Cao, B. Olofsson, S. Gebre-Medhin, M. Pekny, et al. (2001)
Circulation 104, 358-364
   Abstract »    Full Text »    PDF »
Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor.
I. Zachary (2001)
Am J Physiol Cell Physiol 280, C1375-C1386
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VEGFR3 gene structure, regulatory region, and sequence polymorphisms.
K. ILJIN, M. J. KARKKAINEN, E. C. LAWRENCE, M. A. KIMAK, M. UUTELA, J. TAIPALE KATRI PAJUSOLA LEENA ALHONEN, M. HALMEKYTO, D. N. FINEGOLD, R. E. FERRELL, and K. ALITALO (2001)
FASEB J 15, 1028-1036
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Hyperglycemia-Induced Vasculopathy in the Murine Conceptus Is Mediated via Reductions of VEGF-A Expression and VEGF Receptor Activation.
E. Pinter, J. Haigh, A. Nagy, and J. A. Madri (2001)
Am. J. Pathol. 158, 1199-1206
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Adenoviral Expression of Vascular Endothelial Growth Factor-C Induces Lymphangiogenesis in the Skin.
B. Enholm, T. Karpanen, M. Jeltsch, H. Kubo, F. Stenback, R. Prevo, D. G. Jackson, S. Yla-Herttuala, and K. Alitalo (2001)
Circ. Res. 88, 623-629
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Vascular Endothelial Growth Factor C Promotes Tumor Lymphangiogenesis and Intralymphatic Tumor Growth.
T. Karpanen, M. Egeblad, M. J. Karkkainen, H. Kubo, S. Ylä-Herttuala, M. Jäättelä, and K. Alitalo (2001)
Cancer Res. 61, 1786-1790
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Lymphangiogenesis and Tumor Metastasis: Myth or Reality?.
M. S. Pepper (2001)
Clin. Cancer Res. 7, 462-468
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Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability.
D. Fukumura, T. Gohongi, A. Kadambi, Y. Izumi, J. Ang, C.-O. Yun, D. G. Buerk, P. L. Huang, and R. K. Jain (2001)
PNAS 98, 2604-2609
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Molecular mechanisms of blood vessel growth.
E. M. Conway, D. Collen, and P. Carmeliet (2001)
Cardiovasc Res 49, 507-521
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Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family.
I. Zachary and G. Gliki (2001)
Cardiovasc Res 49, 568-581
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The splice variants of vascular endothelial growth factor (VEGF) and their receptors.
C. Robinson and S. Stringer (2001)
J. Cell Sci. 114, 853-865
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VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis.
K. Hamada, Y. Oike, N. Takakura, Y. Ito, L. Jussila, D. J. Dumont, K. Alitalo, and T. Suda (2000)
Blood 96, 3793-3800
   Abstract »    Full Text »    PDF »


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