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T.A. Ciulla, L. Yu, J. Lowe, N. Yu, M. Maia, L.A. Damico, N. Ferrara; Molecular Heterogeneity of VEGF–A in the Vitreous of Patients with Proliferative Diabetic Retinopathy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):967.
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There is compelling evidence that vascular endothelial growth factor–A (VEGF–A) is a key mediator of intraocular neovascularization associated with ischemic retinal diseases and wet age–related macular degeneration. VEGF–A exists as one of several isoforms, of which VEGF–A165 is the most abundant. However, VEGF–A165 may be cleaved at the COOH terminus by various proteases (e.g., plasmin and MMP3) to generate bioactive proteolytic fragments lacking the heparin–binding domain. Previous studies (Aiello et al, NEJM 331:1480–7,1994) demonstrated that the levels of VEGF–A are elevated in the eye fluids of patients with active proliferative retinopathies. However, the assay employed in these early studies had a format that measured intact VEGF–A165 but not VEGF–A121 or proteolytic fragments of VEGF–A165 such as VEGF–A110, thus potentially underestimating the VEGF levels.
To test this hypothesis, we employed a novel multi–site format that measures total VEGF–A, which was used in parallel with the conventional assay to test a panel of vitreous samples.
The levels of "total" VEGF–A were significantly higher than the levels of VEGF–A165, suggesting that a significant portion of VEGF–A is either alternatively spliced VEGF–A121 or – perhaps more likely – proteolytically cleaved VEGF–A. Consistent with this hypothesis, levels of MMP3 and plasminogen in the vitreous of patients with proliferative diabetic retinopathy were significantly higher than control vitreous samples. Furthermore, ion exchange chromatography documented the presence in such vitreous samples of molecular forms of VEGF consistent with VEGFA121 or proteolytic fragments of VEGF–A165.
These findings suggest that non–heparin–binding VEGF–A forms generated by alternative mRNA splicing and/or proteolysis potentially play an important role in pathological neovascularization. Thus, neutralization of such forms of VEGF–A, in addition to VEGF–A165, may be important to achieve optimal clinical benefit.
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