Corneal avascularity is due to soluble VEGF receptor-1

Balamurali K. Ambati, Miho Nozaki, Nirbhai Singh, Atsunobu Takeda, Pooja D. Jani, Tushar Suthar, Romulo J.C. Albuquerque, Elizabeth Richter, Eiji Sakurai, Michael T. Newcomb, Mark E. Kleinman, Ruth B Caldwell, Qing Lin, Yuichiro Ogura, Angela Orecchia, Don A. Samuelson, Dalen W. Agnew, Judy St. Leger, W. Richard Green, Parameshwar J. Mahasreshti & 17 others David T. Curiel, Donna Kwan, Helene Marsh, Sakae Ikeda, Lucy J. Leiper, J. Martin Collinson, Sasha Bogdanovich, Tejvir S. Khurana, Masabumi Shibuya, Megan E. Baldwin, Napoleone Ferrara, Hans Peter Gerber, Sandro De Falco, Jassir Witta, Judit Z. Baffi, Brian J. Raisler, Jayakrishna Ambati

Research output: Contribution to journalArticle

455 Citations (Scopus)

Abstract

Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6 +/- mice and Pax6 +/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6 +/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.

Original languageEnglish (US)
Pages (from-to)993-997
Number of pages5
JournalNature
Volume443
Issue number7114
DOIs
StatePublished - Oct 26 2006

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Vascular Endothelial Growth Factor Receptor-1
Cornea
Trichechus
Sirenia
Vascular Endothelial Growth Factor A
Dugong
Aniridia
Whales
Dolphins
Angiogenesis Inducing Agents
RNA Interference
Neutralizing Antibodies
Blood Vessels
Mammals

ASJC Scopus subject areas

  • General

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Ambati, B. K., Nozaki, M., Singh, N., Takeda, A., Jani, P. D., Suthar, T., ... Ambati, J. (2006). Corneal avascularity is due to soluble VEGF receptor-1. Nature, 443(7114), 993-997. https://doi.org/10.1038/nature05249

Corneal avascularity is due to soluble VEGF receptor-1. / Ambati, Balamurali K.; Nozaki, Miho; Singh, Nirbhai; Takeda, Atsunobu; Jani, Pooja D.; Suthar, Tushar; Albuquerque, Romulo J.C.; Richter, Elizabeth; Sakurai, Eiji; Newcomb, Michael T.; Kleinman, Mark E.; Caldwell, Ruth B; Lin, Qing; Ogura, Yuichiro; Orecchia, Angela; Samuelson, Don A.; Agnew, Dalen W.; St. Leger, Judy; Green, W. Richard; Mahasreshti, Parameshwar J.; Curiel, David T.; Kwan, Donna; Marsh, Helene; Ikeda, Sakae; Leiper, Lucy J.; Collinson, J. Martin; Bogdanovich, Sasha; Khurana, Tejvir S.; Shibuya, Masabumi; Baldwin, Megan E.; Ferrara, Napoleone; Gerber, Hans Peter; De Falco, Sandro; Witta, Jassir; Baffi, Judit Z.; Raisler, Brian J.; Ambati, Jayakrishna.

In: Nature, Vol. 443, No. 7114, 26.10.2006, p. 993-997.

Research output: Contribution to journalArticle

Ambati, BK, Nozaki, M, Singh, N, Takeda, A, Jani, PD, Suthar, T, Albuquerque, RJC, Richter, E, Sakurai, E, Newcomb, MT, Kleinman, ME, Caldwell, RB, Lin, Q, Ogura, Y, Orecchia, A, Samuelson, DA, Agnew, DW, St. Leger, J, Green, WR, Mahasreshti, PJ, Curiel, DT, Kwan, D, Marsh, H, Ikeda, S, Leiper, LJ, Collinson, JM, Bogdanovich, S, Khurana, TS, Shibuya, M, Baldwin, ME, Ferrara, N, Gerber, HP, De Falco, S, Witta, J, Baffi, JZ, Raisler, BJ & Ambati, J 2006, 'Corneal avascularity is due to soluble VEGF receptor-1', Nature, vol. 443, no. 7114, pp. 993-997. https://doi.org/10.1038/nature05249
Ambati BK, Nozaki M, Singh N, Takeda A, Jani PD, Suthar T et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature. 2006 Oct 26;443(7114):993-997. https://doi.org/10.1038/nature05249
Ambati, Balamurali K. ; Nozaki, Miho ; Singh, Nirbhai ; Takeda, Atsunobu ; Jani, Pooja D. ; Suthar, Tushar ; Albuquerque, Romulo J.C. ; Richter, Elizabeth ; Sakurai, Eiji ; Newcomb, Michael T. ; Kleinman, Mark E. ; Caldwell, Ruth B ; Lin, Qing ; Ogura, Yuichiro ; Orecchia, Angela ; Samuelson, Don A. ; Agnew, Dalen W. ; St. Leger, Judy ; Green, W. Richard ; Mahasreshti, Parameshwar J. ; Curiel, David T. ; Kwan, Donna ; Marsh, Helene ; Ikeda, Sakae ; Leiper, Lucy J. ; Collinson, J. Martin ; Bogdanovich, Sasha ; Khurana, Tejvir S. ; Shibuya, Masabumi ; Baldwin, Megan E. ; Ferrara, Napoleone ; Gerber, Hans Peter ; De Falco, Sandro ; Witta, Jassir ; Baffi, Judit Z. ; Raisler, Brian J. ; Ambati, Jayakrishna. / Corneal avascularity is due to soluble VEGF receptor-1. In: Nature. 2006 ; Vol. 443, No. 7114. pp. 993-997.
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abstract = "Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6 +/- mice and Pax6 +/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6 +/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.",
author = "Ambati, {Balamurali K.} and Miho Nozaki and Nirbhai Singh and Atsunobu Takeda and Jani, {Pooja D.} and Tushar Suthar and Albuquerque, {Romulo J.C.} and Elizabeth Richter and Eiji Sakurai and Newcomb, {Michael T.} and Kleinman, {Mark E.} and Caldwell, {Ruth B} and Qing Lin and Yuichiro Ogura and Angela Orecchia and Samuelson, {Don A.} and Agnew, {Dalen W.} and {St. Leger}, Judy and Green, {W. Richard} and Mahasreshti, {Parameshwar J.} and Curiel, {David T.} and Donna Kwan and Helene Marsh and Sakae Ikeda and Leiper, {Lucy J.} and Collinson, {J. Martin} and Sasha Bogdanovich and Khurana, {Tejvir S.} and Masabumi Shibuya and Baldwin, {Megan E.} and Napoleone Ferrara and Gerber, {Hans Peter} and {De Falco}, Sandro and Jassir Witta and Baffi, {Judit Z.} and Raisler, {Brian J.} and Jayakrishna Ambati",
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AU - Nozaki, Miho

AU - Singh, Nirbhai

AU - Takeda, Atsunobu

AU - Jani, Pooja D.

AU - Suthar, Tushar

AU - Albuquerque, Romulo J.C.

AU - Richter, Elizabeth

AU - Sakurai, Eiji

AU - Newcomb, Michael T.

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AU - Orecchia, Angela

AU - Samuelson, Don A.

AU - Agnew, Dalen W.

AU - St. Leger, Judy

AU - Green, W. Richard

AU - Mahasreshti, Parameshwar J.

AU - Curiel, David T.

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AU - Leiper, Lucy J.

AU - Collinson, J. Martin

AU - Bogdanovich, Sasha

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AU - Shibuya, Masabumi

AU - Baldwin, Megan E.

AU - Ferrara, Napoleone

AU - Gerber, Hans Peter

AU - De Falco, Sandro

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AU - Raisler, Brian J.

AU - Ambati, Jayakrishna

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