title: Corneal avascularity is due to soluble VEGF receptor-1.
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.
authors.affiliation: Department of Ophthalmology, Medical College of Georgia & Augusta Veterans Affairs Medical Center, Augusta, Georgia 30907, USA.
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.forename: Miho
authors.initials: M
authors.lastname: Nozaki
authors.forename: Nirbhai
authors.initials: N
authors.lastname: Singh
authors.forename: Atsunobu
authors.initials: A
authors.lastname: Takeda
authors.forename: Pooja D
authors.initials: PD
authors.lastname: Jani
authors.forename: Tushar
authors.initials: T
authors.lastname: Suthar
authors.forename: Romulo J C
authors.initials: RJ
authors.lastname: Albuquerque
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Richter
authors.forename: Eiji
authors.initials: E
authors.lastname: Sakurai
authors.forename: Michael T
authors.initials: MT
authors.lastname: Newcomb
authors.forename: Mark E
authors.initials: ME
authors.lastname: Kleinman
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ogura
authors.forename: Angela
authors.initials: A
authors.lastname: Orecchia
authors.forename: Don A
authors.initials: DA
authors.lastname: Samuelson
authors.forename: Dalen W
authors.initials: DW
authors.lastname: Agnew
authors.forename: Judy
authors.initials: J
authors.lastname: St Leger
authors.forename: W Richard
authors.initials: WR
authors.lastname: Green
authors.forename: Parameshwar J
authors.initials: PJ
authors.lastname: Mahasreshti
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Donna
authors.initials: D
authors.lastname: Kwan
authors.forename: Helene
authors.initials: H
authors.lastname: Marsh
authors.forename: Sakae
authors.initials: S
authors.lastname: Ikeda
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Leiper
authors.forename: J Martin
authors.initials: JM
authors.lastname: Collinson
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.forename: Tejvir S
authors.initials: TS
authors.lastname: Khurana
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Megan E
authors.initials: ME
authors.lastname: Baldwin
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gerber
authors.forename: Sandro
authors.initials: S
authors.lastname: De Falco
authors.forename: Jassir
authors.initials: J
authors.lastname: Witta
authors.forename: Judit Z
authors.initials: JZ
authors.lastname: Baffi
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Raisler
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
mesh_terms: D000818:Animals; D003315:Cornea / Q000098:blood supply* / Q000378:metabolism*; D017353:Gene Deletion; D051379:Mice; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D020455:Trichechus; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1