Study identifies several genes associated with VEGF-induced neovascularization

This experimental study identified several genes associated with changes in vascular endothelial growth factor (VEGF) levels in mice with retinal neovascularization and identified one gene whose association with Müller cells makes it a potential research candidate for diabetic retinopathy treatment.

The Kimba mouse carries a human VEGF transgene causing retinal neovascularization similar to that seen in diabetic retinopathy. The authors examined the relationship between VEGF-induced gene expression changes and structural changes in the retina of juvenile and adult Kimba mice and their wild-type littermates.

An early VEGF spike induced significant long-term retinal neovascularization associated with changes to the retinal ganglion, photoreceptor and Müller cells. Overexpression of VEGF led to dysregulation of photoreceptor metabolism through differential expression of Nr2e3, endothelin 2, betacellulin and semaphorin 3C (sema3C).

Endothelin 2 colocalized to Müller cell end feet and extended into the outer limiting membrane. The authors write that this is perhaps the most exciting finding of this study. These data add further weight to the argument that Edn2 upregulation in Müller cells is a general retinal stress response, and it seems likely that the Edn2/Ednrb system may act as a molecular sensor for retinal stress or injury. This highlights a potential use for Edn2 as an early biomarker for retinal damage, including diabetic retinopathy.

Furthermore, given the speculation that Müller cells could provide effective targets for gene therapy, the upregulation of Edn2 under retinal stress suggests that there may be some therapeutic value in this molecule. Further examination of the processes by which these cells are activated is therefore an important first step in the investigation of this tantalizing prospect.

To the authors' knowledge this is the first report of a relationship between VEGF and Nr2e3, a finding that warrants further studies. They also note that sema3C was identified as significantly differentially expressed by both microarray and qRT-PCR. The involvement of this gene in the Kimba retinal phenotype is further supported by its functional link to the VEGF pathway via the neuropilin receptors.