Role for Extracellular Signal-Responsive Kinase-1 and -2 in Retinal Angiogenesis

作者：Lawrence E. Bullard, Qi Xiang, John S. Penn · 发表于：Investigative Ophthalmology & Visual Science · 年份：2003 · DOI：10.1167/iovs.01-1193 · 被引用次数：82 · 研究领域：Retinopathy of Prematurity Studies、Retinal Development and Disorders、Retinal Diseases and Treatments

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent mitogen for micro- and macrovascular endothelial cells (ECs). Evidence points to a possible role for two mitogen-activated protein (MAP) kinases, the extracellular-signal responsive kinases (ERK)-1 and -2, in VEGF signaling in ECs. This study was undertaken to begin to define the precise role of MAP kinases in VEGF signal transduction related to angiogenesis. METHODS: Bovine retinal microvascular endothelial cells (BRMECs) and a well-established rat model of retinopathy of prematurity (ROP) were used to investigate the role of ERK-1/2 in EC proliferation and tube formation and in retinal angiogenesis in vivo. RESULTS: Administration of VEGF to BRMEC cultures increased ERK-1/2 phosphorylation, cell proliferation, and tube formation in a dose-dependent manner. Phosphorylation of retinal ERK-1/2 also was increased in the ROP model. An inhibitor of ERK, AG126, and an inhibitor of ERK kinase (MEK), PD98059, exhibited a dose-dependent reduction of ERK phosphorylation and EC proliferation, but not tube formation, in VEGF-stimulated BRMECs. In the ROP model, intravitreous injection of 10 micro M AG126 or PD98059 reduced the retinal neovascular area by 71% and 48%, respectfully. No effect was seen on intraretinal blood vessel growth. CONCLUSIONS: These experiments point to a critical role for ERK and MEK in proliferation of ECs, but not in tube formation. Furthermore, inhibition of either of these two signal intermediates ...