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内皮细胞靶向的可溶性人源Delta-like4抑制生理性与病理性眼部血管新生

, PP. 271-278

Keywords: Notch信号通路,人源Delta-like4,精氨酸-甘氨酸-天冬氨酸(RGD)基序,血管新生,脉络膜新生血管形成

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Abstract:

Notch信号通路在血管新生过程中具有重要作用,是治疗病理性血管新生的关键靶标.Notch信号通路的激活与抑制均可阻抑血管新生,但由于体内长期抑制Notch信号通路会导致血管瘤等严重毒副反应,通过激活Notch信号抑制新生血管形成可能更具临床应用价值.然而,目前缺乏可在体内高效活化Notch信号通路的Notch配体.在众多的Notch配体中,Delta-like4(Dll4)特异性表达于血管内皮组织,对血管新生具有关键调控作用.本研究表达并纯化了新型可溶性人源Notch配体hD4R,其由人源Delta-Serrate-Lag-2片段和内皮细胞靶向的精氨酸-甘氨酸-天冬氨酸(RGD)基序组成.实验证实,hD4R可通过其RGD基序与内皮细胞结合,并可有效激活内皮细胞中的Notch信号.平面管腔形成实验和微球萌出实验显示,hD4R能在体外显著抑制血管新生.更为重要的是,hD4R能在体内有效抑制新生鼠视网膜血管新生和激光诱导的脉络膜新生血管形成.综上所述,本研究发明了一种能显著抑制体内外血管生成的可溶性Notch配体hD4R,为治疗过度血管新生性相关疾病提供了新的手段.

References

[1]  1 Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell, 2011, 146: 873-887
[2]  2 Lally D R, Gerstenblith A T, Regillo C D. Preferred therapies for neovascular age-related macular degeneration. Curr Opin Ophthalmol, 2012, 23: 182-188
[3]  3 Benedito R, Hellstr?m M. Notch as a hub for signaling in angiogenesis. Exp Cell Res, 2013, 319: 1281-1288
[4]  4 Kume T. Ligand-dependent Notch signaling in vascular formation. Adv Exp Med Biol, 2012, 727: 210-222
[5]  5 Dou G R, Wang L, Wang Y S, et al. Notch signaling in ocular vasculature development and diseases. Mol Med, 2012, 18: 47-55
[6]  6 Yan M, Callahan C A, Beyer J C, et al. Chronic DLL4 blockade induces vascular neoplasms. Nature, 2010, 463: E6-E7
[7]  7 Fortini M E, Bilder D. Endocytic regulation of Notch signaling. Curr Opin Genet Dev, 2009, 19: 323-328
[8]  8 Danhier F, Breton A L, Préat V. RGD-based strategies to target av b3 integrin in cancer therapy and diagnosis. Mol Pharm, 2012, 9: 2961-2973
[9]  9 Caswell P T, Vadrevu S, Norman J C. Integrins: masters and slaves of endocytic transport. Nat Rev Mol Cell Biol, 2009, 10: 843-853
[10]  10 Zhao X C, Dou G R, Wang L, et al. Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells. Neoplasia, 2013, 15: 815-825
[11]  11 Tian D M, Liang L, Zhao X C, et al. Endothelium-targeted Delta-like 1 promotes hematopoietic stem cell expansion ex vivo and engraftment in hematopoietic tissues in vivo. Stem Cell Res, 2013, 11: 693-706
[12]  12 Dou G R, Wang Y C, Hu X B, et al. RBP-J, the transcription factor downstream of Notch receptors, is essential for the maintenance of vascular homeostasis in adult mice. FASEB J, 2008 22: 1606-1617
[13]  13 Benedito R, Rocha S F, Woeste M, et al. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature, 2012, 484: 110-114
[14]  14 Hellstr?m M, Phng L K, Hofmann J J, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature, 2007, 445: 776-780
[15]  15 Zhang P, Yan X C, Chen Y, et al. Notch signaling in blood vessels: from morphogenesis to homeostasis. Sci China Life Sci, 2014, 57: 774-780
[16]  16 Ridgway J, Zhang G, Wu Y, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature, 2006, 444: 1083-1087
[17]  17 Wu Y, Cain-Hom C, Choy L, et al. Therapeutic antibody targeting of individual Notch receptors. Nature, 2010, 464: 1052-1057
[18]  18 Noguera-Troise I, Daly C, Papadopoulos N J, et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature, 2006, 444: 1032-1037
[19]  19 Yan M. Therapeutic promise and challenges of targeting DLL4/NOTCH1. Vasc Cell, 2011, 3: 17
[20]  20 Scheppke L, Murphy E A, Zarpellon A, et al. Notch promotes vascular maturation by inducing integrin-mediated smooth muscle cell adhesion to the endothelial basement membrane. Blood, 2012, 119: 2149-2158
[21]  21 Bentley K, Franco C A, Philippides A, et al. The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis. Nat Cell Biol, 2014, 16: 309-321
[22]  22 Zhang Y, Dong E. New insight into vascular homeostasis and injury-reconstruction. Sci China Life Sci, 2014, 57: 739-741

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