CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo

F.L. Bos; M. Caunt; J. Peterson-Maduro; L. Planas-Paz; J. Kowalski; T. Karpanen; A. van Impel; R. Tong; J.A. Ernst; J. Korving; J.H. van Es; E. Lammert; H.J. Duckers; S. Schulte-Merker

doi:10.1161/CIRCRESAHA.111.250738

CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo

F.L. Bos, M. Caunt, J. Peterson-Maduro, L. Planas-Paz, J. Kowalski, T. Karpanen, A. van Impel, R. Tong, J.A. Ernst, J. Korving, J.H. van Es, E. Lammert, H.J. Duckers, S. Schulte-Merker

Hubrecht Institute

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Abstract

RATIONALE: Collagen- and calcium-binding EGF domains 1 (CCBE1) has been associated with Hennekam syndrome, in which patients have lymphedema, lymphangiectasias, and other cardiovascular anomalies. Insight into the molecular role of CCBE1 is completely lacking, and mouse models for the disease do not exist. OBJECTIVE: CCBE1 deficient mice were generated to understand the function of CCBE1 in cardiovascular development, and CCBE1 recombinant protein was used in both in vivo and in vitro settings to gain insight into the molecular function of CCBE1. METHODS AND RESULTS: Phenotypic analysis of murine Ccbe1 mutant embryos showed a complete lack of definitive lymphatic structures, even though Prox1(+) lymphatic endothelial cells get specified within the cardinal vein. Mutant mice die prenatally. Proximity ligation assays indicate that vascular endothelial growth factor receptor 3 activation appears unaltered in mutants. Human CCBE1 protein binds to components of the extracellular matrix in vitro, and CCBE1 protein strongly enhances vascular endothelial growth factor-C-mediated lymphangiogenesis in a corneal micropocket assay. CONCLUSIONS: Our data identify CCBE1 as a factor critically required for budding and migration of Prox-1(+) lymphatic endothelial cells from the cardinal vein. CCBE1 probably exerts these effects through binding to components of the extracellular matrix. CCBE1 has little lymphangiogenic effect on its own but dramatically enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Thus, our data suggest CCBE1 to be essential but not sufficient for lymphangiogenesis. [KEYWORDS: Animals, Calcium-Binding Proteins/deficiency/genetics/ physiology, Cornea/blood supply/cytology/metabolism, Endothelium, Lymphatic/ blood supply/cytology/ metabolism, Humans, Lymphangiogenesis/genetics/ physiology, Lymphatic Vessels/ embryology/ metabolism, Mice, Mice, Knockout, Protein Binding/genetics, Tumor Suppressor Proteins/deficiency/genetics/ physiology, Vascular Endothelial Growth Factor C/genetics/ metabolism/physiology]

Original language	English
Pages (from-to)	486-491
Journal	Circulation Research
Volume	109
Issue number	5
DOIs	https://doi.org/10.1161/CIRCRESAHA.111.250738
Publication status	Published - 2011

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Bos, F. L., Caunt, M., Peterson-Maduro, J., Planas-Paz, L., Kowalski, J., Karpanen, T., van Impel, A., Tong, R., Ernst, J. A., Korving, J., van Es, J. H., Lammert, E., Duckers, H. J., & Schulte-Merker, S. (2011). CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circulation Research, 109(5), 486-491. https://doi.org/10.1161/CIRCRESAHA.111.250738

@article{06d8a00525f84db7ad21ef8ea914d22f,

title = "CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo",

abstract = "RATIONALE: Collagen- and calcium-binding EGF domains 1 (CCBE1) has been associated with Hennekam syndrome, in which patients have lymphedema, lymphangiectasias, and other cardiovascular anomalies. Insight into the molecular role of CCBE1 is completely lacking, and mouse models for the disease do not exist. OBJECTIVE: CCBE1 deficient mice were generated to understand the function of CCBE1 in cardiovascular development, and CCBE1 recombinant protein was used in both in vivo and in vitro settings to gain insight into the molecular function of CCBE1. METHODS AND RESULTS: Phenotypic analysis of murine Ccbe1 mutant embryos showed a complete lack of definitive lymphatic structures, even though Prox1(+) lymphatic endothelial cells get specified within the cardinal vein. Mutant mice die prenatally. Proximity ligation assays indicate that vascular endothelial growth factor receptor 3 activation appears unaltered in mutants. Human CCBE1 protein binds to components of the extracellular matrix in vitro, and CCBE1 protein strongly enhances vascular endothelial growth factor-C-mediated lymphangiogenesis in a corneal micropocket assay. CONCLUSIONS: Our data identify CCBE1 as a factor critically required for budding and migration of Prox-1(+) lymphatic endothelial cells from the cardinal vein. CCBE1 probably exerts these effects through binding to components of the extracellular matrix. CCBE1 has little lymphangiogenic effect on its own but dramatically enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Thus, our data suggest CCBE1 to be essential but not sufficient for lymphangiogenesis. [KEYWORDS: Animals, Calcium-Binding Proteins/deficiency/genetics/ physiology, Cornea/blood supply/cytology/metabolism, Endothelium, Lymphatic/ blood supply/cytology/ metabolism, Humans, Lymphangiogenesis/genetics/ physiology, Lymphatic Vessels/ embryology/ metabolism, Mice, Mice, Knockout, Protein Binding/genetics, Tumor Suppressor Proteins/deficiency/genetics/ physiology, Vascular Endothelial Growth Factor C/genetics/ metabolism/physiology]",

author = "F.L. Bos and M. Caunt and J. Peterson-Maduro and L. Planas-Paz and J. Kowalski and T. Karpanen and {van Impel}, A. and R. Tong and J.A. Ernst and J. Korving and {van Es}, J.H. and E. Lammert and H.J. Duckers and S. Schulte-Merker",

note = "Reporting year: 2011",

year = "2011",

doi = "10.1161/CIRCRESAHA.111.250738",

language = "English",

volume = "109",

pages = "486--491",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "Lippincott Williams & Wilkins",

number = "5",

}

Bos, FL, Caunt, M, Peterson-Maduro, J, Planas-Paz, L, Kowalski, J, Karpanen, T, van Impel, A, Tong, R, Ernst, JA, Korving, J, van Es, JH, Lammert, E, Duckers, HJ & Schulte-Merker, S 2011, 'CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo', Circulation Research, vol. 109, no. 5, pp. 486-491. https://doi.org/10.1161/CIRCRESAHA.111.250738

TY - JOUR

T1 - CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo

AU - Bos, F.L.

AU - Caunt, M.

AU - Peterson-Maduro, J.

AU - Planas-Paz, L.

AU - Kowalski, J.

AU - Karpanen, T.

AU - van Impel, A.

AU - Tong, R.

AU - Ernst, J.A.

AU - Korving, J.

AU - van Es, J.H.

AU - Lammert, E.

AU - Duckers, H.J.

AU - Schulte-Merker, S.

N1 - Reporting year: 2011

PY - 2011

Y1 - 2011

N2 - RATIONALE: Collagen- and calcium-binding EGF domains 1 (CCBE1) has been associated with Hennekam syndrome, in which patients have lymphedema, lymphangiectasias, and other cardiovascular anomalies. Insight into the molecular role of CCBE1 is completely lacking, and mouse models for the disease do not exist. OBJECTIVE: CCBE1 deficient mice were generated to understand the function of CCBE1 in cardiovascular development, and CCBE1 recombinant protein was used in both in vivo and in vitro settings to gain insight into the molecular function of CCBE1. METHODS AND RESULTS: Phenotypic analysis of murine Ccbe1 mutant embryos showed a complete lack of definitive lymphatic structures, even though Prox1(+) lymphatic endothelial cells get specified within the cardinal vein. Mutant mice die prenatally. Proximity ligation assays indicate that vascular endothelial growth factor receptor 3 activation appears unaltered in mutants. Human CCBE1 protein binds to components of the extracellular matrix in vitro, and CCBE1 protein strongly enhances vascular endothelial growth factor-C-mediated lymphangiogenesis in a corneal micropocket assay. CONCLUSIONS: Our data identify CCBE1 as a factor critically required for budding and migration of Prox-1(+) lymphatic endothelial cells from the cardinal vein. CCBE1 probably exerts these effects through binding to components of the extracellular matrix. CCBE1 has little lymphangiogenic effect on its own but dramatically enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Thus, our data suggest CCBE1 to be essential but not sufficient for lymphangiogenesis. [KEYWORDS: Animals, Calcium-Binding Proteins/deficiency/genetics/ physiology, Cornea/blood supply/cytology/metabolism, Endothelium, Lymphatic/ blood supply/cytology/ metabolism, Humans, Lymphangiogenesis/genetics/ physiology, Lymphatic Vessels/ embryology/ metabolism, Mice, Mice, Knockout, Protein Binding/genetics, Tumor Suppressor Proteins/deficiency/genetics/ physiology, Vascular Endothelial Growth Factor C/genetics/ metabolism/physiology]

AB - RATIONALE: Collagen- and calcium-binding EGF domains 1 (CCBE1) has been associated with Hennekam syndrome, in which patients have lymphedema, lymphangiectasias, and other cardiovascular anomalies. Insight into the molecular role of CCBE1 is completely lacking, and mouse models for the disease do not exist. OBJECTIVE: CCBE1 deficient mice were generated to understand the function of CCBE1 in cardiovascular development, and CCBE1 recombinant protein was used in both in vivo and in vitro settings to gain insight into the molecular function of CCBE1. METHODS AND RESULTS: Phenotypic analysis of murine Ccbe1 mutant embryos showed a complete lack of definitive lymphatic structures, even though Prox1(+) lymphatic endothelial cells get specified within the cardinal vein. Mutant mice die prenatally. Proximity ligation assays indicate that vascular endothelial growth factor receptor 3 activation appears unaltered in mutants. Human CCBE1 protein binds to components of the extracellular matrix in vitro, and CCBE1 protein strongly enhances vascular endothelial growth factor-C-mediated lymphangiogenesis in a corneal micropocket assay. CONCLUSIONS: Our data identify CCBE1 as a factor critically required for budding and migration of Prox-1(+) lymphatic endothelial cells from the cardinal vein. CCBE1 probably exerts these effects through binding to components of the extracellular matrix. CCBE1 has little lymphangiogenic effect on its own but dramatically enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Thus, our data suggest CCBE1 to be essential but not sufficient for lymphangiogenesis. [KEYWORDS: Animals, Calcium-Binding Proteins/deficiency/genetics/ physiology, Cornea/blood supply/cytology/metabolism, Endothelium, Lymphatic/ blood supply/cytology/ metabolism, Humans, Lymphangiogenesis/genetics/ physiology, Lymphatic Vessels/ embryology/ metabolism, Mice, Mice, Knockout, Protein Binding/genetics, Tumor Suppressor Proteins/deficiency/genetics/ physiology, Vascular Endothelial Growth Factor C/genetics/ metabolism/physiology]

U2 - 10.1161/CIRCRESAHA.111.250738

DO - 10.1161/CIRCRESAHA.111.250738

M3 - Article

SN - 0009-7330

VL - 109

SP - 486

EP - 491

JO - Circulation Research

JF - Circulation Research

IS - 5

ER -

CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo

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