Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology and Pharmacology, School of Veterinary Sciences, University of Bristol, Bristol, UK.
Invest Ophthalmol Vis Sci. 2010 Aug;51(8):4273-81. doi: 10.1167/iovs.09-4296. Epub 2010 Mar 17.
A number of key ocular diseases, including diabetic retinopathy and age-related macular degeneration, are characterized by localized areas of epithelial or endothelial damage, which can ultimately result in the growth of fragile new blood vessels, vitreous hemorrhage, and retinal detachment. VEGF-A(165), the principal neovascular agent in ocular angiogenic conditions, is formed by proximal splice site selection in its terminal exon 8. Alternative splicing of this exon results in an antiangiogenic isoform, VEGF-A(165)b, which is downregulated in diabetic retinopathy. Here the authors investigate the antiangiogenic activity of VEGF(165)b and its effect on retinal epithelial and endothelial cell survival.
VEGF-A(165)b was injected intraocularly in a mouse model of retinal neovascularization (oxygen-induced retinopathy [OIR]). Cytotoxicity and cell migration assays were used to determine the effect of VEGF-A(165)b.
VEGF-A(165)b dose dependently inhibited angiogenesis (IC(50), 12.6 pg/eye) and retinal endothelial migration induced by 1 nM VEGF-A(165) across monolayers in culture (IC(50), 1 nM). However, it also acts as a survival factor for endothelial cells and retinal epithelial cells through VEGFR2 and can stimulate downstream signaling. Furthermore, VEGF-A(165)b injection, while inhibiting neovascular proliferation in the eye, reduced the ischemic insult in OIR (IC(50), 2.6 pg/eye). Unlike bevacizumab, pegaptanib did not interact directly with VEGF-A(165)b.
The survival effects of VEGF-A(165)b signaling can protect the retina from ischemic damage. These results suggest that VEGF-A(165)b may be a useful therapeutic agent in ischemia-induced angiogenesis and a cytoprotective agent for retinal pigment epithelial cells.
一些主要的眼部疾病，包括糖尿病性视网膜病变和年龄相关性黄斑变性，其特征是局部上皮或内皮损伤，最终可导致脆弱的新血管生长、玻璃体积血和视网膜脱离。VEGF-A（165）是眼部血管生成疾病中的主要新生血管因子，它通过其末端外显子 8 的近端剪接位点选择形成。该外显子的选择性剪接导致了一种抗血管生成的异构体 VEGF-A（165）b，其在糖尿病性视网膜病变中下调。作者在此研究了 VEGF（165）b 的抗血管生成活性及其对视网膜上皮细胞和内皮细胞存活的影响。
作者在视网膜新生血管模型（氧诱导的视网膜病变[OIR]）中眼内注射 VEGF-A（165）b。使用细胞毒性和细胞迁移测定来确定 VEGF-A（165）b 的作用。
VEGF-A（165）b 呈剂量依赖性地抑制血管生成（IC50，12.6 pg/眼）和通过 1 nM VEGF-A（165）穿过培养单层诱导的视网膜内皮迁移（IC50，1 nM）。然而，它也作为一种通过 VEGFR2 对内皮细胞和视网膜上皮细胞的生存因子发挥作用，并能刺激下游信号。此外，VEGF-A（165）b 注射虽然抑制了眼中的新生血管增殖，但减轻了 OIR 中的缺血损伤（IC50，2.6 pg/眼）。与 bevacizumab 不同，pegaptanib 不会直接与 VEGF-A（165）b 相互作用。
VEGF-A（165）b 信号的生存效应可以保护视网膜免受缺血损伤。这些结果表明，VEGF-A（165）b 可能是缺血诱导的血管生成的有用治疗剂和视网膜色素上皮细胞的细胞保护剂。
