Blockage of VEGF-Induced Angiogenesis by Preventing VEGF Secretion

摘要: Vascular endothelial growth factor (VEGF)/vascular permeability is one of the most frequently expressed angiogenic factors in several pathological tissues. Development VEGF antagonists has become an important approach treatment angiogenesis-dependent diseases. Here we describe a novel anti-VEGF strategy by preventing secretion VEGF. We utilize fact that placenta (PlGF)-1, member family lacking detectable activity, preferentially forms intracellular heterodimers with cells coexpressing both factors. constructed retroviral vector containing human PlGF-1 or C-terminal KDEL sequence, which mammalian retention signal for endoplasmic reticulum. Transduction murine Lewis lung carcinoma retro-hPlGF-1-KDEL construct almost completely abrogated tumor growth. Consistent dramatic antitumor effect, mouse molecules remained as mVEGF/hPlGF-1 heterodimers, and only negligible amount mVEGF homodimers were secreted. As result, hPlGF-1-KDEL-expressing tumors, blood vessels at very low numbers lacked branching capillary networks. Gene transfer hVEGF-KDEL into likewise produced effect. Thus, our study provides antiangiogenic