Prolactins are natural inhibitors of angiogenesis in the retina
Prolactins are natural inhibitors of angiogenesis in the retina
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DOI：
10.1167/iovs.05-0173
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发表时间：
2005-08-01
影响因子：
4.4
通讯作者：
Clapp, C
中科院分区：
文献类型：
--
作者：
Aranda, J;Rivera, JC;Clapp, C
目的.视网膜的正常抗血管生成环境的破坏导致异常血管生成，这是全世界视力丧失的主要原因。催乳素（PRL），最初与牛奶生产相关的激素，可以被蛋白水解加工成16 K-PRL，这是一种具有强效抗血管生成和血管收缩作用的16 kDa N-末端PRL片段。本研究旨在确定16 K-PRL是否天然存在于视网膜中并在血管生成和血管舒张中发挥作用。用RT-PCR和原位杂交方法检测大鼠视网膜PRL mRNA的表达。Western blot检测视网膜匀浆中PRL及其衍生片段的表达。通过玻璃体内注射针对PRL的抗体或小干扰RNA（siRNA）来研究PRL和16 K-PRL在视网膜中的作用，以抑制视网膜PRL mRNA的表达。大鼠视网膜表达PRL mRNA的外核，外丛状，内核和神经节细胞层。全长PRL和N-末端16 K-PRL检测视网膜匀浆中的多克隆和单克隆抗体。玻璃体内注射能够中和16 K-PRL作用的抗体使视网膜血管和毛细血管面积的数量增加了三倍。此外，siRNA介导的PRL mRNA抑制使视网膜新生血管增加3倍，并导致血管舒张显著增加。这些结果表明，PRL合成和切割抗血管生成的16 K-PRL的视网膜组织，这些分子在防止血管生成在健康的视网膜中发挥关键作用。
PURPOSE. Disruption of the normally antiangiogenic environment of the retina leads to aberrant angiogenesis, the major cause of vision loss throughout the world. Prolactin (PRL), the hormone originally associated with milk production, can be proteolytically processed to 16K-PRL, a 16 kDa N-terminal PRL fragment with potent antiangiogenic and vasoconstrictive actions. This study was conducted to determine whether 16K-PRL is found naturally in the retina and plays a role in angiogenesis and vasodilation.METHODS. Expression of PRL mRNA in rat retina was determined by RT-PCR and in situ hybridization. Western blot was used to examine the expression of PRL and derived fragments in retinal homogenates. The role of PRL and 16K-PRL in the retina was studied by intravitreal injection of either antibodies against PRL or small interfering RNAs ( siRNA), to suppress expression of retinal PRL mRNA.RESULTS. Rat retina expressed PRL mRNA in the outer nuclear, outer plexiform, inner nuclear, and ganglion cell layers. Both full-length PRL and N-terminal 16K-PRL were detected in retinal homogenates by polyclonal and monoclonal antibodies. The intravitreal injection of antibodies able to neutralize the actions of 16K-PRL increased the number of retinal blood vessels and capillary area by threefold. Furthermore, siRNA-mediated inhibition of PRL mRNA increased retinal neovascularization threefold and resulted in a significant increase in vasodilation.CONCLUSIONS. These results demonstrate that PRL is synthesized and cleaved to antiangiogenic 16K-PRL by retinal tissue and that these molecules play a key role in preventing angiogenesis in the healthy retina.