血管内皮细胞特异性过表达Bcl-2与视网膜血管发生的关系及其机制研究
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摘要
第一部分血管内皮细胞特异性过表达Bcl-2对于视网膜正常及异常血管发生的调控
目的：探索血管内皮细胞特异性过表达Bcl-2对于视网膜正常血管发育发生以及病理性新生血管发生的调控。
方法：观测血管内皮细胞特异性过表达Bcl-2小鼠在视网膜血管网正常发育的不同时间点(P7,P14,P21,P42)视网膜铺片染色观测其视网膜血管网发育情况,及在ROP模型中,P12时视网膜无灌注区形成以及P17天时新生血管发生情况。
结果：血管内皮细胞内特异性过表达Bcl-2并不影响视网膜血管网的正常发育。在ROP模型中,血管内皮细胞内特异性过表达Bcl-2对视网膜无灌注区和新生血管形成无显著影响。
结论：血管内皮细胞过表达Bcl-2对于视网膜血管网正常发育及病理性新生血管发生无明显影响。
第二部分血管内皮细胞Bcl-2表达改变对脉络膜新生血管形成影响的初步研究
目的：明确血管内皮细胞特异性过表达Bcl-2及血管内皮细胞特异性敲除Bcl-2与脉络膜新生血管发生的关系
方法：激光诱导小鼠脉络膜新生血管模型,小鼠眼底激光光凝形成三个激光斑,14天后进行脉络膜-巩膜铺片后ICAM-2染色标记脉络膜新生血管,评估血管内皮细胞特异性过表达Bcl-2,血管内皮细胞内特异性敲除Bcl-2对脉络膜新生血管形成的影响。
结果：血管内皮细胞内特异性过表达Bcl-2小鼠脉络膜新生血管面积与WT相比并无明显差异,但血管内皮细胞敲除Bcl-2小鼠中脉络膜新生血管面积与WT相比明显缩小。
结论：血管内皮细胞敲除Bcl-2能抑制脉络膜新生血管发生,而血管内皮细胞过表达Bcl-2并无此作用。
Part I The Correlativity of Overexpression of Bcl-2in Endothelial Cell and Retinal Angiogenesis
Objective:to investigate the physiological role of overexpression of Bcl-2in vascular endothelium in the development of retinal vasculature and retinal neovascularization formation during oxygen-induced ischemic retinopathy (OIR).
Method:We observed the retinal vasculature development of Bcl-2overexpressed in endothelial cells in retinal whole mount slides in different time points (P7, P14, P21, P42), then compare the nonperfusion area and neovascularization with wild type mice in ROP model.
Results:The retinal vascular development did not impacted by the Bcl-2overexpression in endothelial cells. Overexpression of Bcl-2in endothelium can not prevent retinal nonperfusion area or neovascularization formation in ROP.
Conclusions:overexpression of Bcl-2in endothelium have no effect on the retinal vascular development and retinal neovascularization.
Part Ⅱ The Impact of The Change of Bcl-2Content in Endothelial Cells and The Formation of Choroidal Neovascularization
Objectives:To assess the impact of deficiency and overexpression of Bcl-2in endothelial cells on choroidal neovascularization (CNV).
Methods:Three laser burns were placed in each eye in mice to induce CNV. For quantitative measurements of neovascularization, intercellular adhesion molecule2staining was performed at14days postlaser of the choroidal-sclera flat mounts. The CNV area was measured by intercellular adhesion molecule2staining and use of ImageJ software
Results:Deficiency of Bcl-2in endothelial cells exhibited significantly smaller areas of neovascularization on choroidal flat mounts compared with WT mice,however the overexpression of Bcl-2in endothelial cells have the same areas of neovascularization as WT mice.
Conclusions:Deficiency of Bcl-2in endothelial cells contributes to reduced choroidal neovascularization.
目的：探索血管内皮细胞特异性过表达Bcl-2对于视网膜正常血管发育发生以及病理性新生血管发生的调控。
方法：观测血管内皮细胞特异性过表达Bcl-2小鼠在视网膜血管网正常发育的不同时间点(P7,P14,P21,P42)视网膜铺片染色观测其视网膜血管网发育情况,及在ROP模型中,P12时视网膜无灌注区形成以及P17天时新生血管发生情况。
结果：血管内皮细胞内特异性过表达Bcl-2并不影响视网膜血管网的正常发育。在ROP模型中,血管内皮细胞内特异性过表达Bcl-2对视网膜无灌注区和新生血管形成无显著影响。
结论：血管内皮细胞过表达Bcl-2对于视网膜血管网正常发育及病理性新生血管发生无明显影响。
第二部分血管内皮细胞Bcl-2表达改变对脉络膜新生血管形成影响的初步研究
目的：明确血管内皮细胞特异性过表达Bcl-2及血管内皮细胞特异性敲除Bcl-2与脉络膜新生血管发生的关系
方法：激光诱导小鼠脉络膜新生血管模型,小鼠眼底激光光凝形成三个激光斑,14天后进行脉络膜-巩膜铺片后ICAM-2染色标记脉络膜新生血管,评估血管内皮细胞特异性过表达Bcl-2,血管内皮细胞内特异性敲除Bcl-2对脉络膜新生血管形成的影响。
结果：血管内皮细胞内特异性过表达Bcl-2小鼠脉络膜新生血管面积与WT相比并无明显差异,但血管内皮细胞敲除Bcl-2小鼠中脉络膜新生血管面积与WT相比明显缩小。
结论：血管内皮细胞敲除Bcl-2能抑制脉络膜新生血管发生,而血管内皮细胞过表达Bcl-2并无此作用。
Part I The Correlativity of Overexpression of Bcl-2in Endothelial Cell and Retinal Angiogenesis
Objective:to investigate the physiological role of overexpression of Bcl-2in vascular endothelium in the development of retinal vasculature and retinal neovascularization formation during oxygen-induced ischemic retinopathy (OIR).
Method:We observed the retinal vasculature development of Bcl-2overexpressed in endothelial cells in retinal whole mount slides in different time points (P7, P14, P21, P42), then compare the nonperfusion area and neovascularization with wild type mice in ROP model.
Results:The retinal vascular development did not impacted by the Bcl-2overexpression in endothelial cells. Overexpression of Bcl-2in endothelium can not prevent retinal nonperfusion area or neovascularization formation in ROP.
Conclusions:overexpression of Bcl-2in endothelium have no effect on the retinal vascular development and retinal neovascularization.
Part Ⅱ The Impact of The Change of Bcl-2Content in Endothelial Cells and The Formation of Choroidal Neovascularization
Objectives:To assess the impact of deficiency and overexpression of Bcl-2in endothelial cells on choroidal neovascularization (CNV).
Methods:Three laser burns were placed in each eye in mice to induce CNV. For quantitative measurements of neovascularization, intercellular adhesion molecule2staining was performed at14days postlaser of the choroidal-sclera flat mounts. The CNV area was measured by intercellular adhesion molecule2staining and use of ImageJ software
Results:Deficiency of Bcl-2in endothelial cells exhibited significantly smaller areas of neovascularization on choroidal flat mounts compared with WT mice,however the overexpression of Bcl-2in endothelial cells have the same areas of neovascularization as WT mice.
Conclusions:Deficiency of Bcl-2in endothelial cells contributes to reduced choroidal neovascularization.
引文
1. Takeda A, Baffi JZ, Kleinman ME, et al: CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature 2009,460(7252):225-230.
2. Urbich C, Dimmeler S:Endothelial progenitor cells:characterization and role in vascular biology. Circ Res 2004,95(4):343-353.
3. Bikfalvi A:Angiogenesis:molecular mechanisms of activation, promotion and maintenance. Journal of BUON:official journal of the Balkan Union of Oncology2007,12 Suppl 1:S59-66.
4. Kumar P, Ning Y, Polverini PJ:Endothelial cells expressing Bcl-2 promotes tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor invasion. Laboratory investigation; a journal of technical methods and pathology 2008,88(7):740-749.
5. Michaelidis TM, Sendtner M, Cooper JD et al.:Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 1996,17(1):75-89.
6. Zhao H, Yenari MA, Cheng D et al.:Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. Journal of neurochemistry 2003,85(4):1026-1036.
7. Most SP:Facial nerve recovery in bcl2 overexpression mice after crush injury. Archives of facial plastic surgery 2004,6(2):82-87.
8. Chierzi S, Strettoi E, Cenni MC, et al.:Optic nerve crush:axonal responses in wild-type and bcl-2 transgenic mice. The Journal of neuroscience:the official journal of the Society for Neuroscience 1999,19(19):8367-8376.
9. Farlie PG, Dringen R, Rees SM, et al.:Bcl-2 transgene expression can protect neurons against developmental and induced cell death.. Proceedings of the National Academy of Sciences of the United States of America 1995, 92(10):4397-4401.
10. Chen J, Flannery JG, LaVail MM, et al.:bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations. Proceedings of the National Academy of Sciences of the United States of America 1996, 93(14):7042-7047.
11. Reed JC:Bcl-2 family proteins. Oncogene 1998,17(25):3225-3236.
12. Nor JE, Christensen J, Mooney DJ, et al.:Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. The American journal of pathology 1999,154(2):375-384.
13. Gerber HP, Dixit V, Ferrara N:Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. The Journal of biological chemistry 1998,273(21):13313-13316.
14. Karsan A, Yee E, Poirier GG, et al.:Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. The American journal of pathology 1997,151(6):1775-1784.
15. Karl E, Warner K, Zeitlin B, et al: Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. Cancer research 2005,65(12):5063-5069.
16. Gerber HP, McMurtrey A, Kowalski J, et al.:Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. The Journal of biological chemistry 1998,273(46):30336-30343.
17. Dhanabal M, Ramchandran R, Waterman MJ, et al.:Endostatin induces endothelial cell apoptosis. The Journal of biological chemistry 1999, 274(17):11721-11726.
18. Jimenez B, Volpert OV, Crawford SE, et al.:Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature medicine 2000,6(1):41-48.
19. Nor JE, Mitra RS, Sutorik MM,,et al.:Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. Journal of vascular research 2000,37(3):209-218.
20. Karl E, Zhang Z, Dong Z, et al.:Unidirectional crosstalk between Bcl-xL and Bcl-2 enhances the angiogenic phenotype of endothelial cells. Cell death and differentiation 2007,14(9):1657-1666.
21. Segura I, Serrano A, De Buitrago GG, et al.:Inhibition of programmed cell death impairs in vitro vascular-like structure formation and reduces in vivo angiogenesis. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2002,16(8):833-841.
22. Pollman MJ, Naumovski L, Gibbons GH:Endothelial cell apoptosis in capillary network remodeling. Journal of cellular physiology 1999,178(3):359-370.
23. Wang S, Sorenson CM, Sheibani N:Attenuation of retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy in Bcl-2-/-mice. Dev Biol 2005,279(1):205-219.
24. Walsh K, Smith RC, Kim HS:Vascular cell apoptosis in remodeling, restenosis, and plaque rupture. Circ Res 2000,87(3):184-188.
25. Kern TS, Du Y, Miller CM, et al.:Overexpression of Bcl-2 in Vascular Endothelium Inhibits the Microvascular Lesions of Diabetic Retinopathy. The American journal of pathology 2010,176(5):2550-2558.
26. Biroccio A, Candiloro A, Mottolese M, et al.:Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2000,14(5):652-660.
27. Matsushita H, Morishita R, Nata T, et al.:Hypoxia-induced endothelial apoptosis through nuclear factor-kappaB (NF-kappaB)-mediated bcl-2 suppression:in vivo evidence of the importance of NF-kappaB in endothelial cell regulation. Circ Res 2000,86(9):974-981.
28. Schechner JS, Crane SK, Wang F, et al. Engraftment of a vascularized human skin equivalent. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2003,17(15):2250-2256.
29. Kondo S, Tang Y, Scheef EA, et al.:Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2. American journal of physiology Cell physiology 2008,294(6):C1521-1530.
30. Uraoka M, Ikeda K, Kurimoto-Nakano R, et al:Loss of bcl-2 during the senescence exacerbates the impaired angiogenic functions in endothelial cells by deteriorating the mitochondrial redox state. Hypertension 2011, 58(2):254-263.
31. Nor JE, Christensen J, Liu J, et al.:Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer research 2001,61(5):2183-2188.
1. Takeda A, Baffi JZ, Kleinman ME, et al:CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature 2009,460(7252):225-230.
2. Urbich C, Dimmeler S:Endothelial progenitor cells:characterization and role in vascular biology. Circ Res 2004,95(4):343-353.
3. Bikfalvi A:Angiogenesis:molecular mechanisms of activation, promotion and maintenance. Journal of BUON:official journal of the Balkan Union of Oncology 2007,12 Suppl 1:S59-66.
4. Kumar P, Ning Y, Polverini PJ:Endothelial cells expressing Bcl-2 promotes tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor invasion. Laboratory investigation; a journal of technical methods and pathology 2008,88(7):740-749.
5. Michaelidis TM, Sendtner M, Cooper JD, et al:Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 1996,17(l):75-89.
6. Zhao H, Yenari MA, Cheng D, et al:Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. Journal of neurochemistry 2003,85(4):1026-1036.
7. Most SP:Facial nerve recovery in bcl2 overexpression mice after crush injury. Archives of facial plastic surgery 2004,6(2):82-87.
8. Chierzi S, Strettoi E, Cenni MC, et al:Optic nerve crush:axonal responses in wild-type and bcl-2 transgenic mice. The Journal of neuroscience:the official journal of the Society for Neuroscience 1999,19(19):8367-8376.
9. Farlie PG, Dringen R, Rees SM, et al:BCL-2 TRANSGENE EXPRESSION CAN PROTECT NEURONS AGAINST DEVELOPMENTAL AND INDUCED CELL-DEATH. Proceedings of the National Academy of Sciences of the United States of America 1995,92(10):4397-4401.
10. Chen J, Flannery JG, LaVail MM, et al:bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations. Proceedings of the National Academy of Sciences of the United States of America 1996, 93(14):7042-7047.
11. Reed JC:Bcl-2 family proteins. Oncogene 1998,17(25):3225-3236.
12. Nor JE, Christensen J, Mooney DJ, et al:Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. The American journal of pathology 1999,154(2):375-384.
13. Gerber HP, Dixit V, Ferrara N:Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and Al in vascular endothelial cells. The Journal of biological chemistry 1998,273(21):13313-13316.
14. Karsan A, Yee E, Poirier GG, et al:Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. The American journal of pathology 1997,151(6):1775-1784.
15. Karl E, Warner K, Zeitlin B, et al:Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. Cancer research 2005,65(12):5063-5069.
16. Gerber HP, McMurtrey A, Kowalski J, et al:Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. The Journal of biological chemistry 1998,273(46):30336-30343.
17. Dhanabal M, Ramchandran R, Waterman MJ, et al:Endostatin induces endothelial cell apoptosis. The Journal of biological chemistry 1999, 274(17):11721-11726.
18. Jimenez B, Volpert OV, Crawford SE, et al:Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature medicine 2000,6(1):41-48.
19. Nor JE, Mitra RS, Sutorik MM, et al:Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. Journal of vascular research 2000,37(3):209-218.
20. Karl E, Zhang Z, Dong Z, et al:Unidirectional crosstalk between Bcl-xL and Bcl-2 enhances the angiogenic phenotype of endothelial cells. Cell death and differentiation 2007,14(9):1657-1666.
21. Segura I, Serrano A, De Buitrago GG, et al:Inhibition of programmed cell death impairs in vitro vascular-like structure formation and reduces in vivo angiogenesis. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2002,16(8):833-841.
22. Pollman MJ, Naumovski L, Gibbons GH:Endothelial cell apoptosis in capillary network remodeling. Journal of cellular physiology 1999, 178(3):359-370.
23. Wang S, Sorenson CM, Sheibani N:Attenuation of retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy in Bcl-2-/-mice. Dev Biol 2005,279(1):205-219.
24. Walsh K, Smith RC, Kim HS:Vascular cell apoptosis in remodeling, restenosis, and plaque rupture. Circ Res 2000,87(3):184-188.
25. Kern TS, Du Y, Miller CM, et al:Overexpression of Bcl-2 in Vascular Endothelium Inhibits the Microvascular Lesions of Diabetic Retinopathy. The American journal of pathology 2010,176(5):2550-2558.
26. Biroccio A, Candiloro A, Mottolese M, et al:Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2000,14(5):652-660.
27. Matsushita H, Morishita R, Nata T, et al:Hypoxia-induced endothelial apoptosis through nuclear factor-kappaB (NF-kappaB)-mediated bcl-2 suppression:in vivo evidence of the importance of NF-kappaB in endothelial cell regulation. Circ Res 2000,86(9):974-981.
28. Schechner JS, Crane SK, Wang F, et al:Engraftment of a vascularized human skin equivalent. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2003,17(15):2250-2256.
29. Kondo S, Tang Y, Scheef EA, et al:Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2. American journal of physiology Cell physiology 2008,294(6):C1521-1530.
30. Uraoka M, Ikeda K, Kurimoto-Nakano R, et al:Loss of bcl-2 during the senescence exacerbates the impaired angiogenic functions in endothelial cells by deteriorating the mitochondrial redox state. Hypertension 2011, 58(2):254-263.
31. Nor JE, Christensen J, Liu J,et al:Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer research 2001,61(5):2183-2188.
1. Takeda A, Baffi JZ, Kleinman ME, et al:CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature 2009,460(7252):225-230.
2. Holash J, Davis S, Papadopoulos N, et al:VEGF-Trap:a VEGF blocker with potent antitumor effects. Proceedings of the National Academy of Sciences of the United States of America 2002,99(17):11393-11398.
3. Day S, Acquah K, Mruthyunjaya P, et al:Ocular complications after anti-vascular endothelial growth factor therapy in Medicare patients with age-related macular degeneration. American journal of ophthalmology 2011, 152(2):266-272.
4. Nishijima K, Ng YS, Zhong L, et al:Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. The American journal of pathology 2007, 171(1):53-67.
5. Urbich C, Dimmeler S:Endothelial progenitor cells:characterization and role in vascular biology. Circ Res 2004,95(4):343-353.
6. Bikfalvi A:Angiogenesis:molecular mechanisms of activation, promotion and maintenance. Journal of BUON:official journal of the Balkan Union of Oncology 2007,12 Suppl 1:S59-66.
7. Nor JE, Christensen J, Mooney DJ, et al:Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. The American journal of pathology 1999,154(2):375-384.
8. Gerber HP, Dixit V, Ferrara N:Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. The Journal of biological chemistry 1998,273(21):13313-13316.
9. Karsan A, Yee E, Poirier GG, et al:Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. The American journal of pathology 1997,151(6):1775-1784.
10. Karl E, Warner K, Zeitlin B, et al:Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. Cancer research 2005,65(12):5063-5069.
11. Gerber HP, McMurtrey A, Kowalski J, et al:Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. The Journal of biological chemistry 1998,273(46):30336-30343.
12. Dhanabal M, Ramchandran R, Waterman MJ, et al:Endostatin induces endothelial cell apoptosis. The Journal of biological chemistry 1999, 274(17):11721-11726.
13. Jimenez B, Volpert OV, Crawford SE, et al:Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature medicine 2000,6(1):41-48.
14. Farlie PG, Dringen R, Rees SM, et al:BCL-2 TRANSGENE EXPRESSION CAN PROTECT NEURONS AGAINST DEVELOPMENTAL AND INDUCED CELL-DEATH. Proceedings of the National Academy of Sciences of the United States of America 1995,92(10):4397-4401.
15. Nor JE, Mitra RS, Sutorik MM, et al:Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. Journal of vascular research 2000,37(3):209-218.
16. Karl E, Zhang Z, Dong Z, et al:Unidirectional crosstalk between Bcl-xL and Bcl-2 enhances the angiogenic phenotype of endothelial cells. Cell death and differentiation 2007,14(9):1657-1666.
17. Segura I, Serrano A, De Buitrago GG, et al:Inhibition of programmed cell death impairs in vitro vascular-like structure formation and reduces in vivo angiogenesis. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2002,16(8):833-841.
18. Pollman MJ, Naumovski L, Gibbons GH:Endothelial cell apoptosis in capillary network remodeling. Journal of cellular physiology 1999, 178(3):359-370.
19. Wang S, Sorenson CM, Sheibani N:Attenuation of retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy in Bcl-2-/-mice. Dev Biol 2005,279(1):205-219.
20. Umeda N, Kachi S, Akiyama H, et al:Suppression and regression of choroidal neovascularization by systemic administration of an alpha5betal integrin antagonist. Molecular pharmacology 2006,69(6):1820-1828.
21. Kern TS, Du Y, Miller CM, et al:Overexpression of Bcl-2 in Vascular Endothelium Inhibits the Microvascular Lesions of Diabetic Retinopathy. The American journal of pathology 2010,176(5):2550-2558.
22. Biroccio A, Candiloro A, Mottolese M, et al:Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2000,14(5):652-660.
23. Matsushita H, Morishita R, Nata T, et al:Hypoxia-induced endothelial apoptosis through nuclear factor-kappaB (NF-kappaB)-mediated bcl-2 suppression:in vivo evidence of the importance of NF-kappaB in endothelial cell regulation. Circ Res 2000,86(9):974-981.
24. Schechner JS, Crane SK, Wang F, et al:Engraftment of a vascularized human skin equivalent. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2003,17(15):2250-2256.
25. Kondo S, Tang Y, Scheef EA, et al:Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2. American journal of physiology Cell physiology 2008,294(6):C1521-1530.
26. Uraoka M, Ikeda K, Kurimoto-Nakano R, et al:Loss of bcl-2 during the senescence exacerbates the impaired angiogenic functions in endothelial cells by deteriorating the mitochondrial redox state. Hypertension 2011, 58(2):254-263.
27. Nor JE, Christensen J, Liu J, et al:Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer research 2001,61(5):2183-2188.
28. Evans J, Wormald R:Is the incidence of registrable age-related macular degeneration increasing? The British journal of ophthalmology 1996, 80(1):9-14.
29. Ryan SJ:The development of an experimental model of subretinal neovascularization in disciform macular degeneration. Transactions of the American Ophthalmological Society 1979,77:707-745.
30. Dutta D, Ray S, Home P, et al:Regulation of angiogenesis by histone chaperone HIRA-mediated incorporation of lysine 56-acetylated histone H3.3 at chromatin domains of endothelial genes. The Journal of biological chemistry 2010,285(53):41567-41577.
31. Reed JC:Bcl-2 family proteins. Oncogene 1998,17(25):3225-3236.
32. Zeitlin BD, Joo E, Dong Z, et al:Antiangiogenic effect of TW37, a small-molecule inhibitor of Bcl-2. Cancer research 2006,66(17):8698-8706.
1. Kim I, Ryan AM, Rohan R, et al. Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci 1999;40:2115-21.
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2. Urbich C, Dimmeler S:Endothelial progenitor cells:characterization and role in vascular biology. Circ Res 2004,95(4):343-353.
3. Bikfalvi A:Angiogenesis:molecular mechanisms of activation, promotion and maintenance. Journal of BUON:official journal of the Balkan Union of Oncology2007,12 Suppl 1:S59-66.
4. Kumar P, Ning Y, Polverini PJ:Endothelial cells expressing Bcl-2 promotes tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor invasion. Laboratory investigation; a journal of technical methods and pathology 2008,88(7):740-749.
5. Michaelidis TM, Sendtner M, Cooper JD et al.:Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 1996,17(1):75-89.
6. Zhao H, Yenari MA, Cheng D et al.:Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. Journal of neurochemistry 2003,85(4):1026-1036.
7. Most SP:Facial nerve recovery in bcl2 overexpression mice after crush injury. Archives of facial plastic surgery 2004,6(2):82-87.
8. Chierzi S, Strettoi E, Cenni MC, et al.:Optic nerve crush:axonal responses in wild-type and bcl-2 transgenic mice. The Journal of neuroscience:the official journal of the Society for Neuroscience 1999,19(19):8367-8376.
9. Farlie PG, Dringen R, Rees SM, et al.:Bcl-2 transgene expression can protect neurons against developmental and induced cell death.. Proceedings of the National Academy of Sciences of the United States of America 1995, 92(10):4397-4401.
10. Chen J, Flannery JG, LaVail MM, et al.:bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations. Proceedings of the National Academy of Sciences of the United States of America 1996, 93(14):7042-7047.
11. Reed JC:Bcl-2 family proteins. Oncogene 1998,17(25):3225-3236.
12. Nor JE, Christensen J, Mooney DJ, et al.:Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. The American journal of pathology 1999,154(2):375-384.
13. Gerber HP, Dixit V, Ferrara N:Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. The Journal of biological chemistry 1998,273(21):13313-13316.
14. Karsan A, Yee E, Poirier GG, et al.:Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. The American journal of pathology 1997,151(6):1775-1784.
15. Karl E, Warner K, Zeitlin B, et al: Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. Cancer research 2005,65(12):5063-5069.
16. Gerber HP, McMurtrey A, Kowalski J, et al.:Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. The Journal of biological chemistry 1998,273(46):30336-30343.
17. Dhanabal M, Ramchandran R, Waterman MJ, et al.:Endostatin induces endothelial cell apoptosis. The Journal of biological chemistry 1999, 274(17):11721-11726.
18. Jimenez B, Volpert OV, Crawford SE, et al.:Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature medicine 2000,6(1):41-48.
19. Nor JE, Mitra RS, Sutorik MM,,et al.:Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. Journal of vascular research 2000,37(3):209-218.
20. Karl E, Zhang Z, Dong Z, et al.:Unidirectional crosstalk between Bcl-xL and Bcl-2 enhances the angiogenic phenotype of endothelial cells. Cell death and differentiation 2007,14(9):1657-1666.
21. Segura I, Serrano A, De Buitrago GG, et al.:Inhibition of programmed cell death impairs in vitro vascular-like structure formation and reduces in vivo angiogenesis. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2002,16(8):833-841.
22. Pollman MJ, Naumovski L, Gibbons GH:Endothelial cell apoptosis in capillary network remodeling. Journal of cellular physiology 1999,178(3):359-370.
23. Wang S, Sorenson CM, Sheibani N:Attenuation of retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy in Bcl-2-/-mice. Dev Biol 2005,279(1):205-219.
24. Walsh K, Smith RC, Kim HS:Vascular cell apoptosis in remodeling, restenosis, and plaque rupture. Circ Res 2000,87(3):184-188.
25. Kern TS, Du Y, Miller CM, et al.:Overexpression of Bcl-2 in Vascular Endothelium Inhibits the Microvascular Lesions of Diabetic Retinopathy. The American journal of pathology 2010,176(5):2550-2558.
26. Biroccio A, Candiloro A, Mottolese M, et al.:Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2000,14(5):652-660.
27. Matsushita H, Morishita R, Nata T, et al.:Hypoxia-induced endothelial apoptosis through nuclear factor-kappaB (NF-kappaB)-mediated bcl-2 suppression:in vivo evidence of the importance of NF-kappaB in endothelial cell regulation. Circ Res 2000,86(9):974-981.
28. Schechner JS, Crane SK, Wang F, et al. Engraftment of a vascularized human skin equivalent. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2003,17(15):2250-2256.
29. Kondo S, Tang Y, Scheef EA, et al.:Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2. American journal of physiology Cell physiology 2008,294(6):C1521-1530.
30. Uraoka M, Ikeda K, Kurimoto-Nakano R, et al:Loss of bcl-2 during the senescence exacerbates the impaired angiogenic functions in endothelial cells by deteriorating the mitochondrial redox state. Hypertension 2011, 58(2):254-263.
31. Nor JE, Christensen J, Liu J, et al.:Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer research 2001,61(5):2183-2188.
1. Takeda A, Baffi JZ, Kleinman ME, et al:CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature 2009,460(7252):225-230.
2. Urbich C, Dimmeler S:Endothelial progenitor cells:characterization and role in vascular biology. Circ Res 2004,95(4):343-353.
3. Bikfalvi A:Angiogenesis:molecular mechanisms of activation, promotion and maintenance. Journal of BUON:official journal of the Balkan Union of Oncology 2007,12 Suppl 1:S59-66.
4. Kumar P, Ning Y, Polverini PJ:Endothelial cells expressing Bcl-2 promotes tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor invasion. Laboratory investigation; a journal of technical methods and pathology 2008,88(7):740-749.
5. Michaelidis TM, Sendtner M, Cooper JD, et al:Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 1996,17(l):75-89.
6. Zhao H, Yenari MA, Cheng D, et al:Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. Journal of neurochemistry 2003,85(4):1026-1036.
7. Most SP:Facial nerve recovery in bcl2 overexpression mice after crush injury. Archives of facial plastic surgery 2004,6(2):82-87.
8. Chierzi S, Strettoi E, Cenni MC, et al:Optic nerve crush:axonal responses in wild-type and bcl-2 transgenic mice. The Journal of neuroscience:the official journal of the Society for Neuroscience 1999,19(19):8367-8376.
9. Farlie PG, Dringen R, Rees SM, et al:BCL-2 TRANSGENE EXPRESSION CAN PROTECT NEURONS AGAINST DEVELOPMENTAL AND INDUCED CELL-DEATH. Proceedings of the National Academy of Sciences of the United States of America 1995,92(10):4397-4401.
10. Chen J, Flannery JG, LaVail MM, et al:bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations. Proceedings of the National Academy of Sciences of the United States of America 1996, 93(14):7042-7047.
11. Reed JC:Bcl-2 family proteins. Oncogene 1998,17(25):3225-3236.
12. Nor JE, Christensen J, Mooney DJ, et al:Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. The American journal of pathology 1999,154(2):375-384.
13. Gerber HP, Dixit V, Ferrara N:Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and Al in vascular endothelial cells. The Journal of biological chemistry 1998,273(21):13313-13316.
14. Karsan A, Yee E, Poirier GG, et al:Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. The American journal of pathology 1997,151(6):1775-1784.
15. Karl E, Warner K, Zeitlin B, et al:Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. Cancer research 2005,65(12):5063-5069.
16. Gerber HP, McMurtrey A, Kowalski J, et al:Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. The Journal of biological chemistry 1998,273(46):30336-30343.
17. Dhanabal M, Ramchandran R, Waterman MJ, et al:Endostatin induces endothelial cell apoptosis. The Journal of biological chemistry 1999, 274(17):11721-11726.
18. Jimenez B, Volpert OV, Crawford SE, et al:Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature medicine 2000,6(1):41-48.
19. Nor JE, Mitra RS, Sutorik MM, et al:Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. Journal of vascular research 2000,37(3):209-218.
20. Karl E, Zhang Z, Dong Z, et al:Unidirectional crosstalk between Bcl-xL and Bcl-2 enhances the angiogenic phenotype of endothelial cells. Cell death and differentiation 2007,14(9):1657-1666.
21. Segura I, Serrano A, De Buitrago GG, et al:Inhibition of programmed cell death impairs in vitro vascular-like structure formation and reduces in vivo angiogenesis. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2002,16(8):833-841.
22. Pollman MJ, Naumovski L, Gibbons GH:Endothelial cell apoptosis in capillary network remodeling. Journal of cellular physiology 1999, 178(3):359-370.
23. Wang S, Sorenson CM, Sheibani N:Attenuation of retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy in Bcl-2-/-mice. Dev Biol 2005,279(1):205-219.
24. Walsh K, Smith RC, Kim HS:Vascular cell apoptosis in remodeling, restenosis, and plaque rupture. Circ Res 2000,87(3):184-188.
25. Kern TS, Du Y, Miller CM, et al:Overexpression of Bcl-2 in Vascular Endothelium Inhibits the Microvascular Lesions of Diabetic Retinopathy. The American journal of pathology 2010,176(5):2550-2558.
26. Biroccio A, Candiloro A, Mottolese M, et al:Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2000,14(5):652-660.
27. Matsushita H, Morishita R, Nata T, et al:Hypoxia-induced endothelial apoptosis through nuclear factor-kappaB (NF-kappaB)-mediated bcl-2 suppression:in vivo evidence of the importance of NF-kappaB in endothelial cell regulation. Circ Res 2000,86(9):974-981.
28. Schechner JS, Crane SK, Wang F, et al:Engraftment of a vascularized human skin equivalent. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2003,17(15):2250-2256.
29. Kondo S, Tang Y, Scheef EA, et al:Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2. American journal of physiology Cell physiology 2008,294(6):C1521-1530.
30. Uraoka M, Ikeda K, Kurimoto-Nakano R, et al:Loss of bcl-2 during the senescence exacerbates the impaired angiogenic functions in endothelial cells by deteriorating the mitochondrial redox state. Hypertension 2011, 58(2):254-263.
31. Nor JE, Christensen J, Liu J,et al:Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer research 2001,61(5):2183-2188.
1. Takeda A, Baffi JZ, Kleinman ME, et al:CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature 2009,460(7252):225-230.
2. Holash J, Davis S, Papadopoulos N, et al:VEGF-Trap:a VEGF blocker with potent antitumor effects. Proceedings of the National Academy of Sciences of the United States of America 2002,99(17):11393-11398.
3. Day S, Acquah K, Mruthyunjaya P, et al:Ocular complications after anti-vascular endothelial growth factor therapy in Medicare patients with age-related macular degeneration. American journal of ophthalmology 2011, 152(2):266-272.
4. Nishijima K, Ng YS, Zhong L, et al:Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. The American journal of pathology 2007, 171(1):53-67.
5. Urbich C, Dimmeler S:Endothelial progenitor cells:characterization and role in vascular biology. Circ Res 2004,95(4):343-353.
6. Bikfalvi A:Angiogenesis:molecular mechanisms of activation, promotion and maintenance. Journal of BUON:official journal of the Balkan Union of Oncology 2007,12 Suppl 1:S59-66.
7. Nor JE, Christensen J, Mooney DJ, et al:Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. The American journal of pathology 1999,154(2):375-384.
8. Gerber HP, Dixit V, Ferrara N:Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. The Journal of biological chemistry 1998,273(21):13313-13316.
9. Karsan A, Yee E, Poirier GG, et al:Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. The American journal of pathology 1997,151(6):1775-1784.
10. Karl E, Warner K, Zeitlin B, et al:Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. Cancer research 2005,65(12):5063-5069.
11. Gerber HP, McMurtrey A, Kowalski J, et al:Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. The Journal of biological chemistry 1998,273(46):30336-30343.
12. Dhanabal M, Ramchandran R, Waterman MJ, et al:Endostatin induces endothelial cell apoptosis. The Journal of biological chemistry 1999, 274(17):11721-11726.
13. Jimenez B, Volpert OV, Crawford SE, et al:Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature medicine 2000,6(1):41-48.
14. Farlie PG, Dringen R, Rees SM, et al:BCL-2 TRANSGENE EXPRESSION CAN PROTECT NEURONS AGAINST DEVELOPMENTAL AND INDUCED CELL-DEATH. Proceedings of the National Academy of Sciences of the United States of America 1995,92(10):4397-4401.
15. Nor JE, Mitra RS, Sutorik MM, et al:Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. Journal of vascular research 2000,37(3):209-218.
16. Karl E, Zhang Z, Dong Z, et al:Unidirectional crosstalk between Bcl-xL and Bcl-2 enhances the angiogenic phenotype of endothelial cells. Cell death and differentiation 2007,14(9):1657-1666.
17. Segura I, Serrano A, De Buitrago GG, et al:Inhibition of programmed cell death impairs in vitro vascular-like structure formation and reduces in vivo angiogenesis. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2002,16(8):833-841.
18. Pollman MJ, Naumovski L, Gibbons GH:Endothelial cell apoptosis in capillary network remodeling. Journal of cellular physiology 1999, 178(3):359-370.
19. Wang S, Sorenson CM, Sheibani N:Attenuation of retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy in Bcl-2-/-mice. Dev Biol 2005,279(1):205-219.
20. Umeda N, Kachi S, Akiyama H, et al:Suppression and regression of choroidal neovascularization by systemic administration of an alpha5betal integrin antagonist. Molecular pharmacology 2006,69(6):1820-1828.
21. Kern TS, Du Y, Miller CM, et al:Overexpression of Bcl-2 in Vascular Endothelium Inhibits the Microvascular Lesions of Diabetic Retinopathy. The American journal of pathology 2010,176(5):2550-2558.
22. Biroccio A, Candiloro A, Mottolese M, et al:Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2000,14(5):652-660.
23. Matsushita H, Morishita R, Nata T, et al:Hypoxia-induced endothelial apoptosis through nuclear factor-kappaB (NF-kappaB)-mediated bcl-2 suppression:in vivo evidence of the importance of NF-kappaB in endothelial cell regulation. Circ Res 2000,86(9):974-981.
24. Schechner JS, Crane SK, Wang F, et al:Engraftment of a vascularized human skin equivalent. FASEB journal:official publication of the Federation of American Societies for Experimental Biology 2003,17(15):2250-2256.
25. Kondo S, Tang Y, Scheef EA, et al:Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2. American journal of physiology Cell physiology 2008,294(6):C1521-1530.
26. Uraoka M, Ikeda K, Kurimoto-Nakano R, et al:Loss of bcl-2 during the senescence exacerbates the impaired angiogenic functions in endothelial cells by deteriorating the mitochondrial redox state. Hypertension 2011, 58(2):254-263.
27. Nor JE, Christensen J, Liu J, et al:Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer research 2001,61(5):2183-2188.
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