Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth

Romulo J.C. Albuquerque; Takahiko Hayashi; Won Gil Cho; Mark E. Kleinman; Sami Dridi; Atsunobu Takeda; Judit Z. Baffi; Kiyoshi Yamada; Hiroki Kaneko; Martha G. Green; Joe Chappell; Jörg Wilting; Herbert A. Weich; Satoru Yamagami; Shiro Amano; Nobuhisa Mizuki; Jonathan S. Alexander; Martha L. Peterson; Rolf A. Brekken; Masanori Hirashima; Seema Capoor; Tomohiko Usui; Balamurali K. Ambati; Jayakrishna Ambati

doi:10.1038/nm.2018

Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth

Romulo J.C. Albuquerque, Takahiko Hayashi, Won Gil Cho, Mark E. Kleinman, Sami Dridi, Atsunobu Takeda, Judit Z. Baffi, Kiyoshi Yamada, Hiroki Kaneko, Martha G. Green, Joe Chappell, Jörg Wilting, Herbert A. Weich, Satoru Yamagami, Shiro Amano, Nobuhisa Mizuki, Jonathan S. Alexander, Martha L. Peterson, Rolf A. Brekken, Masanori HirashimaSeema Capoor, Tomohiko Usui, Balamurali K. Ambati, Jayakrishna Ambati

Research output: Contribution to journal › Article › peer-review

305 Scopus citations

Abstract

Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessel growth can lead to myriad diseases. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessel growth has not to our knowledge been previously described. We report the existence of a splice variant of the gene encoding vascular endothelial growth factor receptor-2 (Vegfr-2) that encodes a secreted form of the protein, designated soluble Vegfr-2 (sVegfr-2), that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c function. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without affecting blood vasculature. Administration of sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 thus acts as a molecular uncoupler of blood and lymphatic vessels; modulation of sVegfr-2 might have therapeutic effects in treating lymphatic vascular malformations, transplantation rejection and, potentially, tumor lymphangiogenesis and lymphedema.

Original language	English
Pages (from-to)	1023-1030
Number of pages	8
Journal	Nature Medicine
Volume	15
Issue number	9
DOIs	https://doi.org/10.1038/nm.2018
State	Published - Sep 2009

Bibliographical note

Funding Information:
We thank R. Ashery-Padan (Tel Aviv University), P. Gruss (Max Planck Institute) and D.C. Beebe (Washington University) for LeCre mice, R.K. Nordeen (University of Colorado) for Cre plasmid, K. Miyazono (University of Tokyo) for pVegf-c and J.L. Arbiser (Emory University) and C.D. Kontos (Duke University) for endothelial cell lines; R. King, L. Xu, M. McConnell, K. Emerson, A. Blanford, M. Baker, S. Furlow, M. LaFalce and C. Long for technical assistance; and R. Mohan, F. Cambi, S. Bondada, M. Detmar, M.W. Fannon, T.V. Getchell, R.K. Jain, T.S. Khurana, B.J. Raisler, J.E. Springer, P.A. Pearson, C.W. Vander Kooi, J.G. Woodward, A.M. Rao, G.S. Rao, K. Ambati and L. Garcia for valuable discussions. This work was supported by US National Institutes of Health and National Eye Institute grants EY015422, EY018350 and EY018836 to J.A. and EY017182 and EY017950 to B.K.A.; a Research to Prevent Blindness Lew R. Wassermann Merit Award (J.A.); Physician Scientist Awards (J.A., B.K.A.); a Medical Student Fellowship (R.J.C.A.); a departmental unrestricted grant (J.A.); a University of Kentucky University Research Professorship (J.A.); Fight for Sight (R.J.C.A.); Japan Society for the Promotion of Science for Young Scientists (A.T.); a VA Merit Award (B.K.A.); and the US Department of Defense (B.K.A.). J.A. is also supported by the Doris Duke Distinguished Clinical Scientist Award and the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and is the Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair.

Funding

We thank R. Ashery-Padan (Tel Aviv University), P. Gruss (Max Planck Institute) and D.C. Beebe (Washington University) for LeCre mice, R.K. Nordeen (University of Colorado) for Cre plasmid, K. Miyazono (University of Tokyo) for pVegf-c and J.L. Arbiser (Emory University) and C.D. Kontos (Duke University) for endothelial cell lines; R. King, L. Xu, M. McConnell, K. Emerson, A. Blanford, M. Baker, S. Furlow, M. LaFalce and C. Long for technical assistance; and R. Mohan, F. Cambi, S. Bondada, M. Detmar, M.W. Fannon, T.V. Getchell, R.K. Jain, T.S. Khurana, B.J. Raisler, J.E. Springer, P.A. Pearson, C.W. Vander Kooi, J.G. Woodward, A.M. Rao, G.S. Rao, K. Ambati and L. Garcia for valuable discussions. This work was supported by US National Institutes of Health and National Eye Institute grants EY015422, EY018350 and EY018836 to J.A. and EY017182 and EY017950 to B.K.A.; a Research to Prevent Blindness Lew R. Wassermann Merit Award (J.A.); Physician Scientist Awards (J.A., B.K.A.); a Medical Student Fellowship (R.J.C.A.); a departmental unrestricted grant (J.A.); a University of Kentucky University Research Professorship (J.A.); Fight for Sight (R.J.C.A.); Japan Society for the Promotion of Science for Young Scientists (A.T.); a VA Merit Award (B.K.A.); and the US Department of Defense (B.K.A.). J.A. is also supported by the Doris Duke Distinguished Clinical Scientist Award and the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and is the Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair.

Funders	Funder number
Doris Duke Distinguished Clinical
Japan Society for the Promotion of Science for Young Scientists
US Department of Defense
National Institutes of Health (NIH)
National Eye Institute (NEI)	EY017950, RC1EY020442, EY017182, EY018836, EY018350, EY015422
National Eye Institute (NEI)
Burroughs Wellcome Fund
Research to Prevent Blindness
Fight for Sight Inc
University of Kentucky

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm.2018

Cite this

Albuquerque, R. J. C., Hayashi, T., Cho, W. G., Kleinman, M. E., Dridi, S., Takeda, A., Baffi, J. Z., Yamada, K., Kaneko, H., Green, M. G., Chappell, J., Wilting, J., Weich, H. A., Yamagami, S., Amano, S., Mizuki, N., Alexander, J. S., Peterson, M. L., Brekken, R. A., ... Ambati, J. (2009). Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nature Medicine, 15(9), 1023-1030. https://doi.org/10.1038/nm.2018

@article{9193f5decfba48c68bb913e50751c633,

title = "Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth",

abstract = "Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessel growth can lead to myriad diseases. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessel growth has not to our knowledge been previously described. We report the existence of a splice variant of the gene encoding vascular endothelial growth factor receptor-2 (Vegfr-2) that encodes a secreted form of the protein, designated soluble Vegfr-2 (sVegfr-2), that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c function. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without affecting blood vasculature. Administration of sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 thus acts as a molecular uncoupler of blood and lymphatic vessels; modulation of sVegfr-2 might have therapeutic effects in treating lymphatic vascular malformations, transplantation rejection and, potentially, tumor lymphangiogenesis and lymphedema.",

author = "Albuquerque, {Romulo J.C.} and Takahiko Hayashi and Cho, {Won Gil} and Kleinman, {Mark E.} and Sami Dridi and Atsunobu Takeda and Baffi, {Judit Z.} and Kiyoshi Yamada and Hiroki Kaneko and Green, {Martha G.} and Joe Chappell and J{\"o}rg Wilting and Weich, {Herbert A.} and Satoru Yamagami and Shiro Amano and Nobuhisa Mizuki and Alexander, {Jonathan S.} and Peterson, {Martha L.} and Brekken, {Rolf A.} and Masanori Hirashima and Seema Capoor and Tomohiko Usui and Ambati, {Balamurali K.} and Jayakrishna Ambati",

note = "Funding Information: We thank R. Ashery-Padan (Tel Aviv University), P. Gruss (Max Planck Institute) and D.C. Beebe (Washington University) for LeCre mice, R.K. Nordeen (University of Colorado) for Cre plasmid, K. Miyazono (University of Tokyo) for pVegf-c and J.L. Arbiser (Emory University) and C.D. Kontos (Duke University) for endothelial cell lines; R. King, L. Xu, M. McConnell, K. Emerson, A. Blanford, M. Baker, S. Furlow, M. LaFalce and C. Long for technical assistance; and R. Mohan, F. Cambi, S. Bondada, M. Detmar, M.W. Fannon, T.V. Getchell, R.K. Jain, T.S. Khurana, B.J. Raisler, J.E. Springer, P.A. Pearson, C.W. Vander Kooi, J.G. Woodward, A.M. Rao, G.S. Rao, K. Ambati and L. Garcia for valuable discussions. This work was supported by US National Institutes of Health and National Eye Institute grants EY015422, EY018350 and EY018836 to J.A. and EY017182 and EY017950 to B.K.A.; a Research to Prevent Blindness Lew R. Wassermann Merit Award (J.A.); Physician Scientist Awards (J.A., B.K.A.); a Medical Student Fellowship (R.J.C.A.); a departmental unrestricted grant (J.A.); a University of Kentucky University Research Professorship (J.A.); Fight for Sight (R.J.C.A.); Japan Society for the Promotion of Science for Young Scientists (A.T.); a VA Merit Award (B.K.A.); and the US Department of Defense (B.K.A.). J.A. is also supported by the Doris Duke Distinguished Clinical Scientist Award and the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and is the Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair.",

year = "2009",

month = sep,

doi = "10.1038/nm.2018",

language = "English",

volume = "15",

pages = "1023--1030",

number = "9",

}

Albuquerque, RJC, Hayashi, T, Cho, WG, Kleinman, ME, Dridi, S, Takeda, A, Baffi, JZ, Yamada, K, Kaneko, H, Green, MG, Chappell, J, Wilting, J, Weich, HA, Yamagami, S, Amano, S, Mizuki, N, Alexander, JS, Peterson, ML, Brekken, RA, Hirashima, M, Capoor, S, Usui, T, Ambati, BK & Ambati, J 2009, 'Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth', Nature Medicine, vol. 15, no. 9, pp. 1023-1030. https://doi.org/10.1038/nm.2018

TY - JOUR

T1 - Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth

AU - Albuquerque, Romulo J.C.

AU - Hayashi, Takahiko

AU - Cho, Won Gil

AU - Kleinman, Mark E.

AU - Dridi, Sami

AU - Takeda, Atsunobu

AU - Baffi, Judit Z.

AU - Yamada, Kiyoshi

AU - Kaneko, Hiroki

AU - Green, Martha G.

AU - Chappell, Joe

AU - Wilting, Jörg

AU - Weich, Herbert A.

AU - Yamagami, Satoru

AU - Amano, Shiro

AU - Mizuki, Nobuhisa

AU - Alexander, Jonathan S.

AU - Peterson, Martha L.

AU - Brekken, Rolf A.

AU - Hirashima, Masanori

AU - Capoor, Seema

AU - Usui, Tomohiko

AU - Ambati, Balamurali K.

AU - Ambati, Jayakrishna

N1 - Funding Information: We thank R. Ashery-Padan (Tel Aviv University), P. Gruss (Max Planck Institute) and D.C. Beebe (Washington University) for LeCre mice, R.K. Nordeen (University of Colorado) for Cre plasmid, K. Miyazono (University of Tokyo) for pVegf-c and J.L. Arbiser (Emory University) and C.D. Kontos (Duke University) for endothelial cell lines; R. King, L. Xu, M. McConnell, K. Emerson, A. Blanford, M. Baker, S. Furlow, M. LaFalce and C. Long for technical assistance; and R. Mohan, F. Cambi, S. Bondada, M. Detmar, M.W. Fannon, T.V. Getchell, R.K. Jain, T.S. Khurana, B.J. Raisler, J.E. Springer, P.A. Pearson, C.W. Vander Kooi, J.G. Woodward, A.M. Rao, G.S. Rao, K. Ambati and L. Garcia for valuable discussions. This work was supported by US National Institutes of Health and National Eye Institute grants EY015422, EY018350 and EY018836 to J.A. and EY017182 and EY017950 to B.K.A.; a Research to Prevent Blindness Lew R. Wassermann Merit Award (J.A.); Physician Scientist Awards (J.A., B.K.A.); a Medical Student Fellowship (R.J.C.A.); a departmental unrestricted grant (J.A.); a University of Kentucky University Research Professorship (J.A.); Fight for Sight (R.J.C.A.); Japan Society for the Promotion of Science for Young Scientists (A.T.); a VA Merit Award (B.K.A.); and the US Department of Defense (B.K.A.). J.A. is also supported by the Doris Duke Distinguished Clinical Scientist Award and the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and is the Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair.

PY - 2009/9

Y1 - 2009/9

N2 - Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessel growth can lead to myriad diseases. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessel growth has not to our knowledge been previously described. We report the existence of a splice variant of the gene encoding vascular endothelial growth factor receptor-2 (Vegfr-2) that encodes a secreted form of the protein, designated soluble Vegfr-2 (sVegfr-2), that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c function. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without affecting blood vasculature. Administration of sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 thus acts as a molecular uncoupler of blood and lymphatic vessels; modulation of sVegfr-2 might have therapeutic effects in treating lymphatic vascular malformations, transplantation rejection and, potentially, tumor lymphangiogenesis and lymphedema.

AB - Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessel growth can lead to myriad diseases. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessel growth has not to our knowledge been previously described. We report the existence of a splice variant of the gene encoding vascular endothelial growth factor receptor-2 (Vegfr-2) that encodes a secreted form of the protein, designated soluble Vegfr-2 (sVegfr-2), that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c function. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without affecting blood vasculature. Administration of sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 thus acts as a molecular uncoupler of blood and lymphatic vessels; modulation of sVegfr-2 might have therapeutic effects in treating lymphatic vascular malformations, transplantation rejection and, potentially, tumor lymphangiogenesis and lymphedema.

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Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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