2.2 Ang/Tie-2信号传导系统成员在DR中的表达及其对DR的保护作用

    2.2.1 Ang/Tie信号传导系统在DM患者体内的表达变化在DR患者体内Ang/Tie信号传导系统的成员增加。糖尿病眼部重要的并发症是视网膜血管渗漏（血管渗漏是新生血管的标志）和毛细血管无灌注。DR后期一个重要的改变就是视网膜缺血、缺氧、诱导VEGF上调，刺激视网膜新生血管形成，这是缺血诱导血管渗漏的主要原因。

    Takagi等[16]研究显示：人视网膜血管增殖标本中， Ang-2，Tie-2表达均有升高；且在缺血性视网膜疾病所致的视网膜血管增殖膜中Ang-2，Tie-2表达明显高于非缺血性视网膜疾病。支持这一观点的另外一些实验是Chiarelli等[17]于2002年所做测定，他们测定了223个糖尿病（DM）患者的血清Ang（sAng）水平,发现DM儿童Ang血清浓度升高，微血管并发症与血浆Ang水平显著相关，长期严格控制血糖能使Ang浓度下降。Malamitsi- Puchner等[18]发现在胰岛素依赖性糖尿病（IDDM）中，sAng水平显著升高，女性的sAng水平高于男性。与此同时，Ozaki等[19]收集了30例PDR病例和21例增生性玻璃体视网膜病（proliferative vitreoretinopathy, PVR）患者的玻璃体液，经过检测发现Ang水平均有所升高。

    2.2.2 Ang-1对DR的保护作用  在人类和啮齿类动物DR早期就有部分白细胞通过细胞间黏附分子-1（ICAM-1）黏附于视网膜血管并且引致毛细血管阻塞，导致内皮细胞损伤和死亡以及血—视网膜屏障破坏[20,21]。Joussen等[15]发现Ang-1可以阻止和逆转糖尿病视网膜血管病变，在给予糖尿病大鼠模型球内注射不同剂量Ang-1后结果发现：Ang-1可以抑制血—视网膜屏障破坏，并呈剂量依赖性；Ang-1可以保护血管内皮细胞免受白细胞介导的内皮细胞损伤作用；Ang-1可以降低VEGF和ICAM的mRNA和蛋白水平，从而降低Akt激酶活性，降低视网膜内皮型一氧化氮合酶（eNOS）和一氧化氮（NO）水平；Ang-1也可以通过降低视网膜细胞外信号调节激酶（Erk激酶）活性，减少白细胞黏附血管内皮细胞，并抑制该激酶促内皮细胞死亡的作用。

    3 Ang在DR治疗中的展望

    DR早期病理改变为视网膜微血管通透性升高，DR发展到后期，将由NPDR期发展为以视网膜新生血管和纤维化为特征的PDR期，在PDR期视网膜新生血管引起的渗漏对患者的视力影响极大，如果能够有效的抑制视网膜新生血管引起的渗漏必将抑制DR的进一步发展。目前的研究表明，Ang-1具有调节内皮之间、内皮—基质之间相互作用, 促进血管成熟并维持血管结构，在VEGF等生长因子的存在下, 由于其抗凋亡、促内皮迁移的作用, 增强了VEGF的促内皮芽性生长及血管网络形成作用，而Ang-2做为Ang-1的拮抗剂能拮抗Ang-1的这些生物效应。如何在DR的状况下调整Ang/Tie-2信号传导系统各成员的表达及作用，使其在DR早期血管重建，血管稳定，防渗漏中最大程度的发挥有益作用，是一个极有研究价值值得深入研究的问题。

    【参考文献】

    1 Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos CD. Angiopoietin-2, a natural ancagonist for Tie2 that disrupts in vivo angiogenests. Science ,1997;277(5292):55-60

    2 Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos CD. Isolation of angiopoietin-1,a ligand for the Tie2 receptor, by secretion - trap expression cloning. Cell ,1996;87(7):1161-1691

    3 Brownelee M. Biochemistry and molecular cell biology of diabetic complications.Nature ,2001;414(6865):813-820

    4 Valenzuela DM, Griffiths JA, Rojas J, Aldrich TH, Jones PF, Zhou H, McClain J, Copeland NG, Gilbert DJ, Jenkins NA, Huang T, Papadopoulos N, Maisonpierre PC, Davis S, Yancopoulos CD. Angiopoietins 3 and 4:diverging gene counterparts mice and humans. Proc Natl Acad Sci USA ,l999;96(5):l904-l909

    5 Zagzag D, Hooper A, Friedlander DR, Chan W, Holash J, Wiegand SJ, Yancopoulos GD, Grumet M. In Situ expression of Angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp Neurol ,1999;159(2):391-400

    6 Ziegler SF, Bird TA, Schneringer JA, Schooley KA, Baum PR. Molecular cloning and characterization of a novel receptor protein tyrosine kinase from human placenta. Oncogen ,1993;8:663

    7 Runting AS, Stacker SA, Wiks AF. Tie2, a putative protein tyrosine kinase with extracelluar epidermal growth factor homology domains. Mol Cell Biol ,1992;12:1698

    8 Loughna S, Sato TN. Angiopoietin and TIE signaling pathway in vascular development. Matrix Biol ,2001;20(5-6):319-295

    9 Jones N, Master Z, Jones J, Bouchard D, Gunji Y, Sasaki H, Daly R, Alitalo K, Dumont DJ. Identification of Tek/ TIE2 binding partners. J Biol Chem ,1999;274(43):30896-30905

    10 Kim I, Kim HG, So JN, Kim JH, Kwak HJ, Koh GY. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3'-Kinase/Akt signal transduction pathway. Circ Res ,2000;86(1):24-29

    11 Witzenbichler B, Maisonpierre PC, Jones P, Yancopoulos GD, Isner JM. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J Biol Chem ,1998;273:18514-18521

    12 Hachett SF, Ozaki H, Strauss RW, Wahlin K, Suri C, Maisonpierre P, Yancopoulos G, Campochiaro PA. Angiopoietin-2 expression in the retina: upregulation during physiologic and pathologic neovascularization. J Cell Physiol ,2000;184(3):275-284

    13 Hackett SF, Wiegand S, Yancooulos G, Campochiaro PA. Angiopoietin-2 plays an important role in retinal angiogenesis. J Cell Physiol ,2002;192(2):182-187

    14 Umeda N, Ozaki H, Hayashi H, Miyajima-Uchida H, Oshima K. Colocalization of Tie2, angiopoietin 2 and vascular endothelial growth factor in fibrovascular membrane from patients with retinopathy of prematurity. Ophthalmic Res ,2003;35(4):217-223

    15 Joussen AM, Poulaki V, Tsujikawa A, Qin W, Qaum T, Xu Q, Moromizato Y, Bursell SE, Wiegand SJ, Rudge J, Ioffe E, Yancopoulos GD, Adamis AP. Suppression of diabetic retinopathy with angiopoietin-1. Am J Pathol ,2002;160(5):1683-1693

    16 Takagi H, Koyama S, Seike H, Oh H, Otani A, Matsumura M, Honda Y. Potential role of the angiopoietin/Tie2 system in ischemia-induced retinal neovascularization. Invest Ophthalmol Vis Sci ,2003;44(1):393-402

    17 Chiarelli F, Pomilio M, Mohn A, Tumini S, Verrotti A, Mezzetti A, Cipollone F, Wasniewska M, Morgese G, Spagnoli A. Serum angiogenin concentrations in young patients with diabetes mellitus. Eur J Clin Invest ,2002;29:110-114

    18 Malamitsi-Puchner A, Sarandakou A, Dafogianni C, Tziotis J, Bartsocas CS. Serum angiogenin levels in children and adolescents with insulin-dependent diabetes mellitus. Pediatr Res ,1998;43:798-800

    19 Ozaki H, Hayashi H, Oshima K. Angiogenin levels in the vitreous from patients with proliferative diabetic retinopathy. Ophthalmic Res ,1996;28:356-360

    20 Zhao HY, Sun XG. Angiopoietins and corneal neovascularization. Int J Ophthalmol(Guoji Yanke Zazhi) ,2004;4(5):887-890

    21 Zhang XL, Qiu SD, Chen YJ, Sun WT. An overview of the pathogenesis of diabetic retinopathy. Int J Ophthalmol(Guoji Yanke Zazhi) ,2005;5(6):1239-1241

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