Vegf-c signaling pathways through vegfr-2 and vegfr-3 in vasculo-angiogenesis and hematopoeesis

Koichi Hamada, Yuichi Oike, Nobuyuki Takakura, Yasuhiro Ito, Lotta Jussila, Daniel J. Dumont, Kari Alitalo, Toshio Suda

Research output: Contribution to journalArticle

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Abstract

Embryonic development of blood vessels from endothelial cells consists of vasculogenesis and angiogenesis.Vasculo-angiogenesis is regulated by paracrine signals, many of which are protein ligands that bind to and modulate the activity of transmembrane receptor tyrosine kinases (RTKs). Among the vasculo-angiogenic factors, vascular endothelial growth factor (VEGF) family members and their receptors are known to be critical for vasculo-angiogenesis and hematopoiesis. To clarify these functional differences in VEGF-C signaling through VEGFR-2 and VEGFR-3, we analyzed using a coculture of para-aortic splanchnopleural mesoderm (PSp) expiants from mouse embryos with stromal cells (OP9). This culture system is used to assay both vasculo-angiogenesis and hematopoiesis (Immunity 9:677-86, 1998). Vasculogenesis and angiogenesis were evaluated by the extent of vascular bed and network formation, respectively. Addition of VEGF-C to the P-Sp culture enhanced vascular bed formation and suppressed definitive hematopoiesis. Both vascular bed and network formations were completely suppressed by addition of soluble VEGFR-1-Fc competitor protein. Formation of vascular beds but not networks could be rescued by VEGF-C in the presence of the competitor, while both were rescued by VEGF-A. VEGFR-3 deficient embryos show the abnormal vasculature and severe anemia. Consistent with these in vivo findings, vascular bed formation in the P-Sp from the VEGFR-3 deficient embryos was enhanced to that in wild-type or heterozygous embryos and hematopoiesis was severely suppressed. When VEGFR-3-Fc chimeric protein was added to trap endogenous VEGFC in the P-Sp culture of the VEGFR-3 deficient embryos, vascular bed formation was suppressed and hematopoiesis was partially rescued. These results demonstrate that since VEGF-C signaling through VEGFR-2 works synergistically with VEGF-A, the binding of VEGF-C to VEGFR-3 consequently regulates VEGFR-2 signaling. In VEGFR3 deficient embryos, an excess of VEGF-C signals through VEGFR-2 induced the disturbance of vasculogenesis and hematopoiesis during embryogenesis. This indicates that elaborated control through VEGFR-3 signaling is critical in vasculo-angiogenesis and hematopoiesis.

Original languageEnglish
JournalBlood
Volume96
Issue number11 PART I
Publication statusPublished - 2000

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Vascular Endothelial Growth Factor Receptor-3
Vascular Endothelial Growth Factor C
Hematopoiesis
Vascular Endothelial Growth Factor A
Blood Vessels
Vascular Endothelial Growth Factor Receptor-2
Embryonic Structures
Embryonic Development
Vascular Endothelial Growth Factor Receptor-1
Proteins
Angiogenesis Inducing Agents
Endothelial cells
Blood vessels
Receptor Protein-Tyrosine Kinases
Mesoderm
Stromal Cells
Coculture Techniques
Anemia
Immunity
Assays

ASJC Scopus subject areas

  • Hematology

Cite this

Hamada, K., Oike, Y., Takakura, N., Ito, Y., Jussila, L., Dumont, D. J., ... Suda, T. (2000). Vegf-c signaling pathways through vegfr-2 and vegfr-3 in vasculo-angiogenesis and hematopoeesis. Blood, 96(11 PART I).

Vegf-c signaling pathways through vegfr-2 and vegfr-3 in vasculo-angiogenesis and hematopoeesis. / Hamada, Koichi; Oike, Yuichi; Takakura, Nobuyuki; Ito, Yasuhiro; Jussila, Lotta; Dumont, Daniel J.; Alitalo, Kari; Suda, Toshio.

In: Blood, Vol. 96, No. 11 PART I, 2000.

Research output: Contribution to journalArticle

Hamada, K, Oike, Y, Takakura, N, Ito, Y, Jussila, L, Dumont, DJ, Alitalo, K & Suda, T 2000, 'Vegf-c signaling pathways through vegfr-2 and vegfr-3 in vasculo-angiogenesis and hematopoeesis', Blood, vol. 96, no. 11 PART I.
Hamada K, Oike Y, Takakura N, Ito Y, Jussila L, Dumont DJ et al. Vegf-c signaling pathways through vegfr-2 and vegfr-3 in vasculo-angiogenesis and hematopoeesis. Blood. 2000;96(11 PART I).
Hamada, Koichi ; Oike, Yuichi ; Takakura, Nobuyuki ; Ito, Yasuhiro ; Jussila, Lotta ; Dumont, Daniel J. ; Alitalo, Kari ; Suda, Toshio. / Vegf-c signaling pathways through vegfr-2 and vegfr-3 in vasculo-angiogenesis and hematopoeesis. In: Blood. 2000 ; Vol. 96, No. 11 PART I.
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AU - Jussila, Lotta

AU - Dumont, Daniel J.

AU - Alitalo, Kari

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