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