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Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology 5/2012

01.05.2012 | Medical Ophthalmology

A potential therapeutic strategy for inhibition of ocular neovascularization with a new endogenous protein: rhEDI-8t

verfasst von: Ling Zhang, Xi Shen, Qing Lu, Qingwei Zhou, Jiaqi Gu, Renbao Gan, Hui Zhang, Xiaodong Sun, Bing Xie

Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology | Ausgabe 5/2012

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Abstract

Background

Endogenous angiogenesis inhibitors act as natural negative feedback in the focal area during the neovascularization process, and have less interference on physiological angiogenesis, and thus fewer negative side-effects. These inhibitors are potential candidates to combine with or substitutes for current popular anti-angiogenesis treatments to have synergistic effect. In this study, the effects of recombinant endothelial growth inhibitor protein (rhEDI-8t), a novel endogenous protein originated from collagen VIII, was investigated on ocular neovascularization (NV). Endostatin, a well-identified endogenous angiogenesis inhibitor, was compared in parallel and served as a positive control.

Methods

The inhibitory effect of rhEDI-8t on vascular endothelial cells was evaluated by a human umbilical vascular endothelial cells (HUVEC) proliferation test and a bovine aortic endothelial cells (BAEC) migration experiment. The effect of rhEDI-8t on ocular NV was further investigated in mice with choroidal neovascularization (choroidal NV) induced by laser, ischemic retinopathy and transgenic mice with expression of VEGF in photoreceptors (rho/VEGF) respectively.

Results

RhEDI-8t inhibited the growth of HUVECs and migration of BAECs stimulated by basic fibroblast growth factor (bFGF). Mice intravitreally treated with rhEDI-8t showed a significant reduction of choroidal NV, retinal NV and subretinal NV.

Conclusion

Endogenous angiogenesis inhibitor rhEDI-8t showed a potent anti-angiogenesis effect in both in vitro and in vivo experiments. It contributed to the suppression of ocular NV. The study suggested that rhEDI-8t could be a subsidiary potent therapeutic medicine in addition to anti-VEGF therapy in future clinical anti-angiogenesis treatment.
Literatur
1.
Zurück zum Zitat Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186PubMedCrossRef Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186PubMedCrossRef
2.
Zurück zum Zitat Hosseini H, Nejabat M (2007) A potential therapeutic strategy for inhibition of corneal neovascularization with new anti-VEGF agents. Med Hypotheses 68(4):799–801PubMedCrossRef Hosseini H, Nejabat M (2007) A potential therapeutic strategy for inhibition of corneal neovascularization with new anti-VEGF agents. Med Hypotheses 68(4):799–801PubMedCrossRef
3.
Zurück zum Zitat Tobe T, Okamoto N, Vinores MA, Derevjanik NL, Vinores SA, Zack DJ, Campochiaro PA (1998) Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest Ophthalmol Vis Sci 39(1):180–188PubMed Tobe T, Okamoto N, Vinores MA, Derevjanik NL, Vinores SA, Zack DJ, Campochiaro PA (1998) Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest Ophthalmol Vis Sci 39(1):180–188PubMed
4.
Zurück zum Zitat O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88(2):277–285PubMedCrossRef O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88(2):277–285PubMedCrossRef
5.
Zurück zum Zitat Abdollahi A, Hahnfeldt P, Maercker C, Gröne HJ, Debus J, Ansorge W, Folkman J, Hlatky L, Huber PE (2004) Endostatin’s antiangiogenic signaling network. Mol Cell 13(5):649–663PubMedCrossRef Abdollahi A, Hahnfeldt P, Maercker C, Gröne HJ, Debus J, Ansorge W, Folkman J, Hlatky L, Huber PE (2004) Endostatin’s antiangiogenic signaling network. Mol Cell 13(5):649–663PubMedCrossRef
6.
Zurück zum Zitat Ramchandran R, Dhanabal M, Volk R, Waterman MJ, Segal M, Lu H, Knebelmann B, Sukhatme VP (1999) Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem Biophys Res Commun 255(3):735–739PubMedCrossRef Ramchandran R, Dhanabal M, Volk R, Waterman MJ, Segal M, Lu H, Knebelmann B, Sukhatme VP (1999) Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem Biophys Res Commun 255(3):735–739PubMedCrossRef
7.
Zurück zum Zitat Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, Volk R, Zamborsky ED, Herman S, Sarkar PK, Ericksen MB, Dhanabal M, Simons M, Post M, Kufe DW, Weichselbaum RR, Sukhatme VP, Kalluri R (2000) Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res 60(9):2520–2526PubMed Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, Volk R, Zamborsky ED, Herman S, Sarkar PK, Ericksen MB, Dhanabal M, Simons M, Post M, Kufe DW, Weichselbaum RR, Sukhatme VP, Kalluri R (2000) Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res 60(9):2520–2526PubMed
8.
Zurück zum Zitat Xu R, Yao ZY, Xin L, Zhang Q, Li TP, Gan RB (2001) NC1 domain of human type VIII collagen (alpha 1) inhibits bovine aortic endothelial cell proliferation and causes cell apoptosis. Biochem Biophys Res Commun 289(1):264–268PubMedCrossRef Xu R, Yao ZY, Xin L, Zhang Q, Li TP, Gan RB (2001) NC1 domain of human type VIII collagen (alpha 1) inhibits bovine aortic endothelial cell proliferation and causes cell apoptosis. Biochem Biophys Res Commun 289(1):264–268PubMedCrossRef
10.
Zurück zum Zitat Shono T, Kanetake H, Kanda S (2001) The role of mitogen activated protein kinase activation within focal adhesions in chemotaxis toward FGF-2 by murine brain capillary endothelial cells. Exp Cell Res 264:275–283PubMedCrossRef Shono T, Kanetake H, Kanda S (2001) The role of mitogen activated protein kinase activation within focal adhesions in chemotaxis toward FGF-2 by murine brain capillary endothelial cells. Exp Cell Res 264:275–283PubMedCrossRef
11.
Zurück zum Zitat Kiec-Wilk B, Grzybowska-Galuszka J, Polus A, Pryjma J, Knapp A, Kristiansen K (2010) The MAPK-dependent regulation of the Jagged/notch gene expression by VEGF, bFGF or PPAR gamma mediated angiogenesis in HUVEC. J Physiol Pharmacol 61(2):217–225PubMed Kiec-Wilk B, Grzybowska-Galuszka J, Polus A, Pryjma J, Knapp A, Kristiansen K (2010) The MAPK-dependent regulation of the Jagged/notch gene expression by VEGF, bFGF or PPAR gamma mediated angiogenesis in HUVEC. J Physiol Pharmacol 61(2):217–225PubMed
12.
Zurück zum Zitat Okamoto N, Tobe T, Hackett SF, Ozaki H, Vinores MA, LaRochelle W, Zack DJ, Campochiaro PA (1997) Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol 151(1):281–291PubMed Okamoto N, Tobe T, Hackett SF, Ozaki H, Vinores MA, LaRochelle W, Zack DJ, Campochiaro PA (1997) Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol 151(1):281–291PubMed
13.
Zurück zum Zitat Mendrinos E, Petropoulos IK, Mangioris G, Papadopoulou DN, Stangos AN, Pournaras CJ (2008) Lactate-induced retinal arteriolar vasodilation implicates neuronal nitric oxide synthesis in minipigs. Invest Ophthalmol Vis Sci 49(11):5060–5066PubMedCrossRef Mendrinos E, Petropoulos IK, Mangioris G, Papadopoulou DN, Stangos AN, Pournaras CJ (2008) Lactate-induced retinal arteriolar vasodilation implicates neuronal nitric oxide synthesis in minipigs. Invest Ophthalmol Vis Sci 49(11):5060–5066PubMedCrossRef
14.
Zurück zum Zitat Tobe T, Ortega S, Luna JD, Derevjanik NL, Vinores SA, Zack DJ, Vinores SA, Basilico C, Campochiaro PA (1998) Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. Am J Pathol 153(5):1641–1646PubMedCrossRef Tobe T, Ortega S, Luna JD, Derevjanik NL, Vinores SA, Zack DJ, Vinores SA, Basilico C, Campochiaro PA (1998) Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. Am J Pathol 153(5):1641–1646PubMedCrossRef
15.
Zurück zum Zitat Das A, McGuire PG (2003) Retinal and choroidal angiogenesis: pathophysiology and strategies for inhibition. Progr Retin Eye Res 22(6):721–748CrossRef Das A, McGuire PG (2003) Retinal and choroidal angiogenesis: pathophysiology and strategies for inhibition. Progr Retin Eye Res 22(6):721–748CrossRef
16.
Zurück zum Zitat Campochiaro PA, Hackett SF (2003) Ocular neovascularization: a valuable model system. Oncogene 22(42):6537–6548PubMedCrossRef Campochiaro PA, Hackett SF (2003) Ocular neovascularization: a valuable model system. Oncogene 22(42):6537–6548PubMedCrossRef
17.
Zurück zum Zitat Mori K, Ando A, Gehlbach P, Nesbitt D, Takahashi K, Goldsteen D, Penn M, Chen CT, Mori K, Melia M, Phipps S, Moffat D, Brazzell K, Liau G, Dixon KH, Campochiaro PA (2001) Inhibition of choroidal neovascularization by intravenous injection of adenoviral vectors expressing secretable endostatin. Am J Pathol 159(1):313–320PubMedCrossRef Mori K, Ando A, Gehlbach P, Nesbitt D, Takahashi K, Goldsteen D, Penn M, Chen CT, Mori K, Melia M, Phipps S, Moffat D, Brazzell K, Liau G, Dixon KH, Campochiaro PA (2001) Inhibition of choroidal neovascularization by intravenous injection of adenoviral vectors expressing secretable endostatin. Am J Pathol 159(1):313–320PubMedCrossRef
18.
Zurück zum Zitat Noma H, Funatsu H, Yamashita H, Kitano S, Mishima HK, Hori S (2002) Regulation of angiogenesis in diabetic retinopathy: possible balance between vascular endothelial growth factor and endostatin. Arch Ophthalmol 120(8):1075–1080PubMed Noma H, Funatsu H, Yamashita H, Kitano S, Mishima HK, Hori S (2002) Regulation of angiogenesis in diabetic retinopathy: possible balance between vascular endothelial growth factor and endostatin. Arch Ophthalmol 120(8):1075–1080PubMed
19.
Zurück zum Zitat Bhutto IA, Kim SY, McLeod DS, Merges C, Fukai N, Olsen BR, Lutty GA (2004) Localization of collagen XVIII and the endostatin portion of collagen XVIII in aged human control eyes and eyes with age-related macular degeneration. Invest Ophthalmol Vis Sci 45(5):1544–1552PubMedCrossRef Bhutto IA, Kim SY, McLeod DS, Merges C, Fukai N, Olsen BR, Lutty GA (2004) Localization of collagen XVIII and the endostatin portion of collagen XVIII in aged human control eyes and eyes with age-related macular degeneration. Invest Ophthalmol Vis Sci 45(5):1544–1552PubMedCrossRef
20.
Zurück zum Zitat Ferreras M, Felbor U, Lenhard T, Olsen BR, Delaissé J (2000) Generation and degradation of human endostatin proteins by various proteinases. FEBS Lett 486(3):247–251PubMedCrossRef Ferreras M, Felbor U, Lenhard T, Olsen BR, Delaissé J (2000) Generation and degradation of human endostatin proteins by various proteinases. FEBS Lett 486(3):247–251PubMedCrossRef
21.
Zurück zum Zitat Lee SJ, Jang JW, Kim YM, Lee HI, Jeon JY, Kwon YG, Lee ST (2002) Endostatin binds to the catalytic domain of matrix metalloproteinase-2. FEBS Lett 519(1–3):147–152PubMedCrossRef Lee SJ, Jang JW, Kim YM, Lee HI, Jeon JY, Kwon YG, Lee ST (2002) Endostatin binds to the catalytic domain of matrix metalloproteinase-2. FEBS Lett 519(1–3):147–152PubMedCrossRef
22.
Zurück zum Zitat Nyberg P, Xie L, Kalluri R (2005) Endogenous inhibitors of angiogenesis. Cancer Res 65:3967–3979PubMedCrossRef Nyberg P, Xie L, Kalluri R (2005) Endogenous inhibitors of angiogenesis. Cancer Res 65:3967–3979PubMedCrossRef
23.
Zurück zum Zitat Zatterstrom UK, Felbor U, Fukai N, Olsen BR (2000) Collagen XVIII/endostatin structure and functional role in angiogenesis. Cell Struct Funct 25:97–101PubMedCrossRef Zatterstrom UK, Felbor U, Fukai N, Olsen BR (2000) Collagen XVIII/endostatin structure and functional role in angiogenesis. Cell Struct Funct 25:97–101PubMedCrossRef
24.
Zurück zum Zitat Ni Q, Ji H, Zhao Z, Fan X, Xu C (2009) Endostar, a modified endostatin inhibits non small cell lung cancer cell in vitro invasion through osteopontin-related mechanism. Eur J Pharmacol 614(1–3):1–6PubMedCrossRef Ni Q, Ji H, Zhao Z, Fan X, Xu C (2009) Endostar, a modified endostatin inhibits non small cell lung cancer cell in vitro invasion through osteopontin-related mechanism. Eur J Pharmacol 614(1–3):1–6PubMedCrossRef
25.
Zurück zum Zitat Bai RZ, Wu Y, Liu Q, Xie K, Wei YQ, Wang YS, Liu K, Luo Y, Su JM, Hu B, Liu JY, Li Q, Niu T, Zhao ZW, Yang L (2009) Suppression of lung cancer in murine model: treated by combination of recombinant human endostsatin adenovirus with low-dose cisplatin. J Exp Clin Cancer Res 5:28–31 Bai RZ, Wu Y, Liu Q, Xie K, Wei YQ, Wang YS, Liu K, Luo Y, Su JM, Hu B, Liu JY, Li Q, Niu T, Zhao ZW, Yang L (2009) Suppression of lung cancer in murine model: treated by combination of recombinant human endostsatin adenovirus with low-dose cisplatin. J Exp Clin Cancer Res 5:28–31
26.
Zurück zum Zitat Ouyang XS, Wang X, Ling MT, Wong HL, Tsao SW, Wong YC (2002) Id-1 stimulates serum independent prostate cancer cell proliferation through inactivation of p16 (INK4a)/pRB pathway. Carcinogenesis 23(5):721–725PubMedCrossRef Ouyang XS, Wang X, Ling MT, Wong HL, Tsao SW, Wong YC (2002) Id-1 stimulates serum independent prostate cancer cell proliferation through inactivation of p16 (INK4a)/pRB pathway. Carcinogenesis 23(5):721–725PubMedCrossRef
27.
Zurück zum Zitat Ling MT, Wang X, Ouyang XS, Lee TK, Fan TY, Xu K, Tsao SW, Wong YC (2002) Activation of MAPK signaling pathway is essential for Id-1 induced serum independent prostate cancer cell growth. Oncogene 21(55):8498–8505PubMedCrossRef Ling MT, Wang X, Ouyang XS, Lee TK, Fan TY, Xu K, Tsao SW, Wong YC (2002) Activation of MAPK signaling pathway is essential for Id-1 induced serum independent prostate cancer cell growth. Oncogene 21(55):8498–8505PubMedCrossRef
28.
Zurück zum Zitat Seo MS, Kwak N, Ozaki H, Yamada H, Okamoto N, Yamada E, Fabbro D, Hofmann F, Wood JM, Campochiaro PA (1999) Dramatic inhibition of retinal and choroidal neovascularization by oral administration of a kinase inhibitor. Am J Pathol 154(6):1743–1753PubMedCrossRef Seo MS, Kwak N, Ozaki H, Yamada H, Okamoto N, Yamada E, Fabbro D, Hofmann F, Wood JM, Campochiaro PA (1999) Dramatic inhibition of retinal and choroidal neovascularization by oral administration of a kinase inhibitor. Am J Pathol 154(6):1743–1753PubMedCrossRef
29.
Zurück zum Zitat Lu F, Adelman RA (2009) Are intravitreal bevacizumab and ranibizumab effective in a rat model of choroidal neovascularization? Graefes Arch Clin Exp Ophthalmol 247(2):171–177PubMedCrossRef Lu F, Adelman RA (2009) Are intravitreal bevacizumab and ranibizumab effective in a rat model of choroidal neovascularization? Graefes Arch Clin Exp Ophthalmol 247(2):171–177PubMedCrossRef
30.
Zurück zum Zitat O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79(2):315–328PubMedCrossRef O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79(2):315–328PubMedCrossRef
31.
Zurück zum Zitat O’Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J (1999) Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 285(5435):1926–1928PubMedCrossRef O’Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J (1999) Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 285(5435):1926–1928PubMedCrossRef
32.
Zurück zum Zitat Maione TE, Gray GS, Petro J, Hunt AJ, Donner AL, Bauer SI, Carson HF, Sharpe RJ (1990) Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 247(4938):77–79PubMedCrossRef Maione TE, Gray GS, Petro J, Hunt AJ, Donner AL, Bauer SI, Carson HF, Sharpe RJ (1990) Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 247(4938):77–79PubMedCrossRef
33.
Zurück zum Zitat Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285(5425):245–248PubMedCrossRef Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285(5425):245–248PubMedCrossRef
Metadaten
Titel
A potential therapeutic strategy for inhibition of ocular neovascularization with a new endogenous protein: rhEDI-8t
verfasst von
Ling Zhang
Xi Shen
Qing Lu
Qingwei Zhou
Jiaqi Gu
Renbao Gan
Hui Zhang
Xiaodong Sun
Bing Xie
Publikationsdatum
01.05.2012
Verlag
Springer-Verlag
Erschienen in
Graefe's Archive for Clinical and Experimental Ophthalmology / Ausgabe 5/2012
Print ISSN: 0721-832X
Elektronische ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-011-1765-y

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