Yumiko Saishin

VEGF‐TRAPR1R2 suppresses choroidal neovascularization and VEGF‐induced breakdown of the blood–retinal barrier

Vascular endothelial growth factor (VEGF) plays a central role in the development of retinal neovascularization and diabetic macular edema. There is also evidence suggesting that VEGF is an important stimulator for choroidal neovascularization. In this study, we investigated the effect of a specific inhibitor of VEGF, VEGF‐TRAPR1R2, in models for these disease processes. VEGF‐TRAPR1R2 is a fusion protein, which combines ligand binding elements taken from the extracellular domains of VEGF receptors 1 and 2 fused to the Fc portion of IgG1. Subcutaneous injections or a single intravitreous injection of VEGF‐TRAPR1R2 strongly suppressed choroidal neovascularization in mice with laser‐induced rupture of Bruchs membrane. Subcutaneous injection of VEGF‐TRAPR1R2 also significantly inhibited subretinal neovascularization in transgenic mice that express VEGF in photoreceptors. In two models of VEGF‐induced breakdown of the blood–retinal barrier (BRB), one in which recombinant VEGF is injected into the vitreous cavity and one in which VEGF expression is induced in the retina in transgenic mice, VEGF‐TRAPR1R2 significantly reduced breakdown of the BRB. These data confirm that VEGF is a critical stimulus for the development of choroidal neovascularization and indicate that VEGF‐TRAPR1R2 may provide a new agent for consideration for treatment of patients with choroidal neovascularization and diabetic macular edema.

Inhibition of protein kinase C decreases prostaglandin-induced breakdown of the blood-retinal barrier.

Breakdown of the blood‐retinal barrier (BRB) occurs in several retinal diseases and is a major cause of visual loss. Vascular endothelial growth factor (VEGF) has been implicated as a cause of BRB breakdown in diabetic retinopathy and other ischemic retinopathies, and there is evidence to suggest that other vasopermeability factors may act indirectly through VEGF. In this study, we investigated the effect of several receptor kinase inhibitors on BRB breakdown resulting from VEGF, tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), insulin‐like growth factor‐1 (IGF‐1), prostaglandin E1 (PGE1), or PGE2. Inhibitors of VEGF receptor kinase, including PKC412, PTK787, and SU1498, decreased VEGF‐induced breakdown of the BRB. None of the inhibitors blocked leakage caused by TNF‐α, IL‐1β, or IGF‐1 and only PKC412, an inhibitor of protein kinase C (PKC) as well as VEGF and platelet‐derived growth factor (PDGF) receptor kinases, decreased leakage caused by prostaglandins. Since the other inhibitors of VEGF and/or PDGF receptor kinases that do not also inhibit PKC had no effect on prostaglandin‐induced breakdown of the BRB, these data implicate PKC in retinal vascular leakage caused by prostaglandins. PKC412 may be useful for treatment of post‐operative and inflammatory macular edema, in which prostaglandins play a role, as well as macular edema associated with ischemic retinopathies.

Intraocular gutless adenoviral-vectored VEGF stimulates anterior segment but not retinal neovascularization

Vascular endothelial growth factor (VEGF) and insulin‐like growth factor‐1 (IGF‐1) have been implicated as important stimulatory factors for retinal neovascularization. In this study, we used intraocular gene transfer with gutless adenoviral (AGV) vectors to determine the effect of increased intraocular expression of VEGF, IGF‐1, or sphingosine kinase (SPK), which produces sphingosine‐1‐phosphate, another angiogenic factor. Retinal neovascularization did not occur from intravitreous AGV‐vectored VEGF, IGF‐1, SPK, or combined VEGF and IGF‐1, except occasionally adjacent to the retinal penetration site from the injection. However, corneal and iris neovascularization occurred after 2 weeks in all eyes injected with AGV.VEGF, but not those injected with only AGV.IGF‐1 or AGV.SPK. These data suggest that the superficial capillary bed of the retina is relatively insensitive to VEGF, IGF‐1, or SPK in adult mice, except when combined with retinal trauma. However, AGV‐vectored VEGF is sufficient to consistently cause severe corneal and iris neovascularization. This provides a model for anterior segment neovascularization, which unlike previous models is relatively inexpensive and is not plagued by spontaneous regression, and therefore, may be useful for identification of new treatments.