Hepatocyte growth factor is upregulated in ischemic retina and contributes to retinal vascular leakage and neovascularization

Abstract

In patients with macular edema due to ischemic retinopathy, aqueous levels of hepatocyte growth factor (HGF) correlate with edema severity. We tested whether HGF expression and activity in mice with oxygen-induced ischemic retinopathy supports a role in macular edema. In ischemic retina, HGF was increased in endogenous cells and macrophages associated with retinal neovascularization (NV). HGF activator was increased in and around retinal vessels potentially providing vascular targeting. One day after intravitreous injection of HGF, VE-cadherin was reduced and albumin levels in retina and vitreous were significantly increased indicating vascular leakage. Injection of VEGF caused higher levels of vitreous albumin than HGF, and co-injection of both growth factors caused significantly higher levels than either alone. HGF increased the number of macrophages on the retinal surface, which was blocked by anti-c-Met and abrogated in chemokine (C-C motif) ligand 2 (CCL2)−/− mice. Injection of anti-c-Met significantly decreased leakage within 24 hours and after 5 days it reduced retinal NV in mice with ischemic retinopathy, but had no effect on choroidal NV. These data indicate that HGF is a pro-permeability, pro-inflammatory, and pro-angiogenic factor and along with its activator is increased in ischemic retina providing support for a potential role of HGF in macular edema in ischemic retinopathies.