Hepatocyte growth factor induces retinal vascular permeability via MAP-kinase and PI-3 kinase without altering retinal hemodynamics.

PURPOSE: Although vascular endothelial growth factor (VEGF) is a key mediator of retinal vascular permeability (RVP), there may be additional humoral contributors. Hepatocyte growth factor (HGF) induces endothelial cell separation, regulates expression of cell adhesion molecules and is increased in the vitreous fluid of patients with proliferative diabetic retinopathy. The purpose of this study was to evaluate the in vivo effects of HGF on RVP and retinal hemodynamics and delineate the signaling pathways. METHODS: RVP was assessed by vitreous fluorescein fluorophotometry in rats. Time course and dose-response were determined after intravitreal HGF injection. MAP kinase (MAPK), phosphatidylinositol 3-kinase (PI-3 kinase), and protein kinase C (PKC) involvement were examined by using selective inhibitors. Retinal blood flow (RBF) and mean circulation time (MCT) were evaluated by video fluorescein angiography. RESULTS: HGF increased RVP in a time- and dose-dependent manner. HGF-induced RVP was evident 5 minutes after injection, and reached maximal levels after 25 minutes (+107% versus vehicle, P=0.002). This effect was comparable to that of maximum VEGF stimulation (134%+/-128% at 25 ng/mL). Selective inhibitors of MAPK (PD98059) and PI-3 kinase (LY294002) suppressed HGF-induced RVP by 86%+/-44% (P=0.015) and 97%+/-59% (P=0.021), respectively. Non-isoform-selective inhibition of PKC did not significantly decrease HGF-induced RVP. Although VEGF increases RBF and reduces MCT, HGF did not affect either. CONCLUSIONS: HGF increases RVP in a time- and dose-dependent manner at physiologically relevant concentrations with a magnitude and profile similar to that of VEGF, without affecting retinal hemodynamics. Thus, HGF may represent another clinically significant contributor to retinal edema distinct from the actions of VEGF.

Rapid and durable recovery of visual function in a patient with von hippel-lindau syndrome after systemic therapy with vascular endothelial growth factor receptor inhibitor su5416.

PURPOSE: To present a case of rapid and durable recovery of visual function in a patient with von Hippel-Lindau syndrome and optic nerve head hemangioblastoma after systemic treatment with the vascular endothelial growth factor (VEGF) receptor inhibitor SU5416. DESIGN: Interventional case report. METHODS: Visual function parameters, including visual acuity, automated visual field, and contrast sensitivity, were evaluated using standardized methods repeatedly over a 15-month period. Fundus photographs and fluorescein angiograms were also obtained. Central nervous system lesions were monitored by computed tomography (CT) and magnetic resonance imaging (MRI) scans. Treatment involved the systemic administration of the VEGF receptor inhibitor SU5416. MAIN OUTCOME MEASURES: Clinical presentation, visual acuity using Early Treatment Diabetic Retinopathy Study protocol, Humphrey automated perimetry, (Zeiss Humphrey Systems, Dublin, CA) Vistech contrast sensitivity (Vistech Consultants Inc., Dayton, OH) Farnsworth (Farnsworth-Munsell Color Services, New Windsor, NY) dichotomous panel D-15, retinal photography, fluorescein angiography, and CT and MRI scans. RESULTS: Within 4 weeks of therapy, visual acuity had improved from 20/32(-2) to 20/16(-1), the visual field had expanded from being circumferentially constricted to within 8 degrees of fixation to normal, and contrast sensitivity improved in all but the lowest spatial frequency (1.5 cycles/degree). No change was observed in lesion size by fundus photography. Improvement has been maintained over 18 months with intermittent SU5416 therapy. CONCLUSIONS: We report rapid, extensive, and durable recovery of visual function after systemic administration of the VEGF receptor inhibitor SU5416 to a patient with VHL syndrome and optic nerve head hemangioblastoma. These findings suggest that continued evaluation of VEGF inhibitors for ocular neovascular disorders is warranted.