Intravitreal injection of plasminogen kringle 5, an endogenous angiogenic inhibitor, arrests retinal neovascularization in rats
Intravitreal injection of plasminogen kringle 5, an endogenous angiogenic inhibitor, arrests retinal neovascularization in rats
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DOI：
10.1007/s001250051685
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发表时间：
2001-06-01
期刊：
影响因子：
8.2
通讯作者：
Ma, JX
中科院分区：
文献类型：
--
作者：
Zhang, D;Kaufman, PL;Ma, JX
目的/假设。纤溶酶原Kringle 5是一种内源性血管生成抑制剂。本研究的目的是探讨Kringle 5在视网膜新生血管治疗中的潜在应用。纤溶酶原kringle 5在E.大肠杆菌中进行亲和纯化。在培养的原代人毛细血管内皮细胞中测定其抗血管生成活性。通过高氧暴露和常氧暴露诱导新生大鼠视网膜新生血管形成。将Kringle 5玻璃体内注射到大鼠模型中。视网膜新生血管通过荧光素血管造影在平板视网膜上显示，并通过计数视网膜前血管细胞进行定量。纤溶酶原kringle 5抑制原代内皮细胞，但不抑制视网膜神经元细胞，表明细胞类型特异性抑制。氧诱导的视网膜病变大鼠模型显示血管内皮生长因子的过度表达，视网膜前新生血管和出血。在新生血管形成之前玻璃体内注射Kringle 5导致比注射PBS的对照大鼠更少的新生血管簇和视网膜前血管细胞（p < 0.01）。此外，在新生血管形成后注射Kringle 5抑制视网膜前血管细胞的增加（p < 0.05）。这些结果表明Kringle 5既防止视网膜新生血管的发展又阻止其进展。Kringle 5的注射没有导致视网膜中任何可检测到的炎症反应或对视网膜神经元和预先存在的血管的组织学毒性。这些观察结果表明，玻璃体内递送血管生成抑制剂可能对视网膜的新生血管疾病具有治疗益处。
Aims/hypothesis. Plasminogen kringle 5 is an endogenous angiogenic inhibitor. The purpose of the present study was to explore the potential application of kringle 5 in the treatment of retinal neovascularization.Methods. Plasminogen kringle 5 was expressed in E. coli and affinity-purified. Its anti-angiogenic activity was determined in cultured primary human capillary endothelial cells. Retinal neovascularization was induced in newborn rats by exposure to hyperoxia and then normoxia. Kringle 5 was intravitreally injected into the rat model. Retinal neovascularization was visualized by fluorescein angiography on flat-mounted retina and quantified by counting preretinal vascular cells.Results. Plasminogen kringle 5 inhibited primary endothelial cells but not retinal neuronal cells, suggesting cell type-specific inhibition. The oxygen-induced retinopathy rat model showed an over-expression of vascular endothelial growth factor, preretinal neovascularization and haemorrhage. Intravitreal injection of kringle 5 before the development of neovascularization resulted in fewer neovascular tufts and pre-retinal vascular cells than in control rats with PBS injection (p < 0.01). Moreover, injection of kringle 5 after the development of neovascularization inhibited the increase in the preretinal vascular cells (p < 0.05). These results suggest that kringle 5 both prevents the development and arrests the progression of retinal neovascularization. The injection of kringle 5 did not result in any detectable inflammatory response in the retina or histological toxicity to retina neurons and pre-existing vessels.Conclusion/interpretation. These observations suggest that intravitreal delivery of angiogenic inhibitors could have therapeutic benefits in neovascular diseases of the retina.