神经轴突导向因子Slit2和受体Robo1、Robo4调控角膜血管新生
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摘要
背景与目的：角膜病是世界三大致盲眼病之一,中国公民因单眼和双眼角膜病致盲的盲人约四百万,占眼科致盲眼病的第2位。新生血管是角膜病致盲的主要原因,但其机制至今尚未完全清楚,目前亦无理想治疗方法,因此探索角膜新生血管形成机制及其防治措施具有重要的理论价值和实际意义。为了从全新的角度阐明角膜新生血管的分子机制,我们关注到与血管具有相似结构的系统——神经系统。在生物体内,神经和血管不但距离很近,而且彼此存在很多的关联,具有解剖的相似性和功能的平行性。鉴于神经和血管行为的相似性,两个系统可能共享相同的信号分子。目前已证实四个神经轴突导向因子家族同时调节血管发育,即Ephrins，Semaphorins, Netrins和Slits。我们将目标定位于神经系统中仅有单向调控作用的Slit及其受体Roundabout(Robo)家族。本研究将探讨神经轴突导向因子Slit2和Robo受体是否参与了角膜新生血管形成。方法：角膜囊袋法诱导大鼠角膜新生血管模型,实时荧光定量PCR测定Slit2和Robo 1-4在正常角膜与新生血管角膜的差异表达,免疫组化法和原位杂交法定位。体外培养原代的脐静脉内皮细胞,RT-PCR测定细胞Robo 1-4受体的表达。制备重组的人Slit2蛋白,测定其对血管内皮细胞迁移的影响。结果：大鼠新生血管角膜的Slit2表达量仅为正常角膜的55%,Robo1和Robo4受体表达量分别为正常角膜的2.7倍和1.77倍,差异呈显著性(P<0.05)。Slit2、Robo1和Robo4受体均表达于正常角膜上皮层的全层。随着新生血管区角膜基质中血管内皮细胞侵入的增加,上皮层表达Slit2. Robo1和Robo4减少,而基质层血管内皮细胞表达Robo1和Robo4增多。原代的脐静脉内皮细胞仅表达Robo1和Robo4受体,且重组的人Slit2能抑制脐静脉内皮细胞的移行(P＜0.05)。结论：本研究首次探讨了神经轴突导向因子Slit2与角膜新生血管的关系。研究发现：Slit2通过Robo1、Robo4受体介导抑制角膜病理性新生血管过程,其可能成为角膜新生血管治疗的新靶点。
Background and Objective:Corneal diseases, which include infections, chemical and mechanical injuries, immunologic diseases and degenerations, are a major cause of blindness worldwide. Corneal neovascularization (NV) is involved in many corneal diseases as an important pathological process. Although a number of regulatory factors have been identified to play a role, the molecular mechanisms of corneal NV are still not fully understood and there is no ideal therapy for corneal NV currently as a result. Therefore, further investigation of pathological mechanisms that control corneal NV is needed to improve our understanding of this complex process. To elucidate the molecular mechanisms of corneal NV from a whole new angle, we focus our attention on the nervous system that possesses similar structure to the vascular system. Nerves and blood vessels are in close proximity and in connection with each other, sharing anatomical similarities and functional parallels. Given the behavioral similarities between nervous and vascular system, there may be molecular cross talk and common cues. Four families of classical neuronal guidance cues have so far been identified as regulators of vascular development:the Ephrins, Netrins, Semaphorins and Slits. We focus on the Slits family that regulates monodirectionally in nervous system. Our objective was to investigate whether neuronal guidance cue Slit2 and Roundabout (Robo) receptors are involved in corneal NV. Methods:Corneal NV model in rats was induced by implantation of agarose-coated gelfoam pellets containing basic fibroblast growth factor (bFGF) into corneal stroma. Differential expression of Slit2 and Robol-4 between normal and neovascularized cornea was detected by real-time RT-PCR and visualized by immunohistochemistry and in situ hybridization. Primary human umbilical vein endothelial cells (HUVECs) were harvested and their expression of Robol-4 was detected by RT-PCR. Recombinant human Slit2 protein was prepared and the effect of it on the migration of vascular endothelial cells was examined using cell migration assay. Results:Agarose-coated gelfoam pellets were able to induce well-localized and reproducible corneal NV model. A significant down-regulation of Slit2 and a strong up-regulation of Robol and Robo4 were seen in neovascularized cornea when compared with normal cornea (P<0.05). Slit2, Robol and Robo4 were throughout the epithelium in normal cornea and markedly weak or absent in epithelium in neovascularized cornea, with Robol and Robo4 being prominent in vascular endothelial cells invading the stroma. Primary HUVECs were confirmed to express both Robol and Robo4 receptors and their migration was inhibited by Slit2 (P<0.05). Conclusion:This is the first study to assess the association between Slit2 and corneal NV. Our findings suggest that the interaction of Slit2 with Robol and Robo4 receptors plays an essential role in inhibiting pathological neovascular processes of the cornea and may represent a new therapeutic target for corneal NV.
Background and Objective:Corneal diseases, which include infections, chemical and mechanical injuries, immunologic diseases and degenerations, are a major cause of blindness worldwide. Corneal neovascularization (NV) is involved in many corneal diseases as an important pathological process. Although a number of regulatory factors have been identified to play a role, the molecular mechanisms of corneal NV are still not fully understood and there is no ideal therapy for corneal NV currently as a result. Therefore, further investigation of pathological mechanisms that control corneal NV is needed to improve our understanding of this complex process. To elucidate the molecular mechanisms of corneal NV from a whole new angle, we focus our attention on the nervous system that possesses similar structure to the vascular system. Nerves and blood vessels are in close proximity and in connection with each other, sharing anatomical similarities and functional parallels. Given the behavioral similarities between nervous and vascular system, there may be molecular cross talk and common cues. Four families of classical neuronal guidance cues have so far been identified as regulators of vascular development:the Ephrins, Netrins, Semaphorins and Slits. We focus on the Slits family that regulates monodirectionally in nervous system. Our objective was to investigate whether neuronal guidance cue Slit2 and Roundabout (Robo) receptors are involved in corneal NV. Methods:Corneal NV model in rats was induced by implantation of agarose-coated gelfoam pellets containing basic fibroblast growth factor (bFGF) into corneal stroma. Differential expression of Slit2 and Robol-4 between normal and neovascularized cornea was detected by real-time RT-PCR and visualized by immunohistochemistry and in situ hybridization. Primary human umbilical vein endothelial cells (HUVECs) were harvested and their expression of Robol-4 was detected by RT-PCR. Recombinant human Slit2 protein was prepared and the effect of it on the migration of vascular endothelial cells was examined using cell migration assay. Results:Agarose-coated gelfoam pellets were able to induce well-localized and reproducible corneal NV model. A significant down-regulation of Slit2 and a strong up-regulation of Robol and Robo4 were seen in neovascularized cornea when compared with normal cornea (P<0.05). Slit2, Robol and Robo4 were throughout the epithelium in normal cornea and markedly weak or absent in epithelium in neovascularized cornea, with Robol and Robo4 being prominent in vascular endothelial cells invading the stroma. Primary HUVECs were confirmed to express both Robol and Robo4 receptors and their migration was inhibited by Slit2 (P<0.05). Conclusion:This is the first study to assess the association between Slit2 and corneal NV. Our findings suggest that the interaction of Slit2 with Robol and Robo4 receptors plays an essential role in inhibiting pathological neovascular processes of the cornea and may represent a new therapeutic target for corneal NV.
引文
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