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Br J Ophthalmol. 2007 April; 91(4): 412–413.
PMCID: PMC1994727

Eyes wide s‐flt: clearly, avascular fidelity is a vascular endothelial growth factor family affair

Short abstract

Soluble vascular endothelial growth factor receptor‐1 (s‐flt) may be critical for a variety of human corneal angiogenic conditions

Every year, numerous patients successfully receive corneal transplants because this tissue is both immunologically privileged and it has a remarkable resilience to injury induced neovascularisation.1 The biological explanation of this gift to man and woman in their quest for sustaining life‐long vision, enabling corneal transplantation and the more recent corrective vision surgery a reality, has thus far remained an enigma. Notwithstanding, the search for molecules that allow the cornea to preserve its avascular status has rifled through a long list of known antiangiogenic agents, but the testing of experimental mouse models of their deficiencies have all come up without suitable answers.2 This negated explanation for a single gene product being responsible for corneal avascularity spawned the next logical idea that biological redundancies in antiangiogenesis could explain the mystical properties of the cornea. Now, contrary to this belief, Ambati et al, looking at eyes from a wide range of mammalian species, have concluded in a recent report that such a formidable antiangiogenic role is, after all, a vascular endothelial growth factor (VEGF) family affair; the bastion of cornea avascularity is soluble VEGF receptor‐1 (s‐flt).3 In this issue (see page 505), Ambati et al provide important proof as to why it is this molecule that needs to be considered critical for a variety of human corneal angiogenic conditions.4

The VEGF family, comprised of VEGF‐A, ‐B, ‐C, ‐D and placental growth factor, exhibit specific and varied levels of affinity for their receptors, VEGFR1, VEGFR2 and VEGFR3.5 Clearly, the requirement for VEGF is so critical to mammalian development that even loss of a single allele of its gene results in embryonic fatality.6 Therefore, it is ironic that the principal angiogenic stimulator VEGF‐A is present in the avascular cornea. It is this conundrum that set Ambati et al to suggest that not only humans, but other mammals that depend on visual acuity for survival may have adapted mechanisms to counteract VEGF‐A in the cornea. Those honed in the yin and yang of the angiogenic balance hypothesis proposed by Judah Folkman7 will find vindication that these investigators discovered Nature's choice to select s‐flt as the VEGF‐A trap in the cornea, no doubt the antagonistic receptor with the highest binding affinity for VEGF‐A. Indeed, the Kd for ligand binding of VEGF‐A for VEGFR1 is approximately 2–10 pM, which is an order of magnitude higher than that for VEGFR2.8,9 s‐FLT is formed by alternative splicing of the pre‐RNA and its expression serves as a natural dominant‐negative inhibitor of VEGF action because this spliced variant lacks the vital transmembrane and kinase domain found in membrane bound VEGFR1 (mbFlt‐1)10; embraced in this molecular coitus with s‐Flt, VEGF‐A is thus retained inactive.3

This rationale sounds good for the uninjured cornea where tissue homeostasis levels of VEGF‐A are counterbalanced by s‐Flt. But what happens when mutations in genes unrelated to vascular development severely compromise corneal epithelial barrier or structural functions causing chronic inflammation to ensue and leading to corneal angiogenesis? To gain support for their hypothesis that it is diminished s‐flt levels that make VEGF‐A become bioavailable, Ambati et al assessed vascularised corneas of humans suffering from aniridia, a congenital disease caused by mutations in the gene encoding a master eye transcription factor pax‐6.11,12 Patients with aniridia suffer from multiple eye problems because PAX‐6 regulates developmentally controlled pathways that contribute to eye morphogenesis.13 This disease is manifested by the smaller size of the globe or “small eye” with differing levels of penetrance of the disorder, most often being characterised by a rudimentary iris. Interestingly, this disease is also naturally found in many other species that present with similar pathogenic anomalies as the human counterpart,12 with the Sey mouse being a popular rodent model that has been relatively well characterised.14 Thus, when a collection of human aniridia corneas were investigated it was found that s‐flt levels were dramatically lowered compared with those from normal human corneas, suggesting that vascularisation of human aniridia may also be regulated by this molecule.

Could these findings have broader impact on other clinical manifestations that are known to elicit neovascularisation? When these investigators looked at samples from a series of patients having alkali burn injuries or those afflicted by interstitial keratitis, this theme of an s‐flt regulated corneal avascular ambit was reinforced. Indeed, s‐flt levels are found decreased in corneas that become vascularised because of chemical injury, while on the contrary, s‐flt levels are shown to be returned to normal in spontaneous resolution of childhood keratitis. These findings suggest modalities to restore s‐flt levels in the cornea to combat the potent angiogenic actions of endogenous VEGF‐A,15 and that produced also by recruited inflammatory cells could serve many clinical applications in antiangiogenesis.

The meeting place for over three decades for testing hypotheses on the roles and efficacies of quite a diversity of angiogenesis modulators has sought the innate vascular resistance of the cornea,16,17 all the while unknowing of the mechanisms of how this tissue serves in this dutiful role. Now that the mask has been lifted on this mystery of Fidelio,18 we hope that the lesson learned about corneal avascular fidelity will shape treatments to prevent blindness from corneal angiogenesis, and in seeking this ultimate clinical goal let us not forget to return this investment to our brethren who donate their eyes for research.


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