蛋白激酶C-α在重组血管抑素抑制兔耳创面愈合中的作用
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摘要
目的研究PKC-a在重组血管抑素(Recombinant Human Angiostatin, rh-AS)(K1-3)影响兔耳皮肤创面愈合和血管增生中的作用。
方法构建兔耳腹侧皮肤创面愈合模型。创面分别给予PBS液(对照组)、rh-AS(K1-3)(rh-AS组)、PMA (PMA组)、Go6983(Go6983组)、rh-AS联合PMA (rh-AS+PMA组)和rh-AS联合Go6983(rh-AS+Go6983组)湿敷,每日1次,连续13-16天(上皮化)。分别于伤后3天、7天、11天,采集创面图像,用Image-Pro Plus6.0图像处理软件计算创面愈合率,并记录各组创面愈合时间。于伤后第3天、7天、11天、上皮化时切取创面标本,采用CD34免疫组化染色检测微血管密度变化,用免疫组化方法半定量检测各时间点创面组织中PKC-a表达情况。创面愈合时间、创面愈合率、微血管密度及PKC-a阳性细胞比例均采用单因素方差分析,组间两两比较采用LSD法检验,若方差不齐则采用Kruskal-Wallis检验；P<0.05表示差异有统计学意义。
结果1rh-AS组和G66983组创面愈合时间长于对照组而PMA组创面愈合时间短于对照组(P<0.05)；rh-AS组创面愈合时间长于rh-AS+PMA组,但较rh-AS+Go6983组缩短(P<0.05)；PMA组创面愈合时间短于rh-AS+PMA组(P<0.05)；G66983组创面愈合时间较rh-AS+Go6983组缩短(P<0.05)。
2.伤后第3天各组间创面愈合率无差异(P>0.05)。伤后第7天：rh-AS组、G66983组创面愈合率小于对照组,而PMA组则高于对照组(P＜0.05); rh-AS组创面愈合率低于rh-AS+PMA组,而高于rh-AS+Go6983组(P＜0.05); PMA组创面愈合率高于rh-AS+PMA组(P<0.05)；G66983组创面愈合率高于rh-AS+Go6983组(P<0.05)。伤后第11天：rh-AS组、G66983组创面愈合率低于对照组(P<0.05),PMA组高于对照组(P<0.05)；rh-AS组创面愈合率高于rh-AS+Go6983组(P<0.05)；PMA组创面愈合率高于rh-AS+PMA组(P<0.05)；Go6983组创面愈合率高于rh-AS+Go6983组(P<0.05)。
3.微血管密度测定：伤后3天、7天、11天各组创面比较,rh-AS组、G66983组、rh-AS+PMA组、rh-AS+Go6983组微血管密度小于对照组(P<0.05),PMA组血管增生显著高于对照组及其余各组(P<0.05)。各组创面上皮化时,新生血管也随之退化：各组微血管密度下降,但PMA组微血管密度仍高于各组(P<0.05)。
4.PKC-α广泛表达于创面组织细胞,随创面愈合过程进展,各组PKC-α表达增强,阳性细胞(成纤维细胞、内皮细胞、表皮细胞)比例增加。同一时间点组间比较,rh-AS组PKC-α表达水平与对照组无差异(P>0.05),PMA组、rh-AS+PMA组各时间点PKC-α阳性细胞比例均高于对照组和rh-AS组,Go6983组、rh-AS+Go6983组低于对照组和rh-AS组(P<0.05)。
结论1.血管抑素抑制创面愈合过程中血管增生,延迟创面愈合。2. PKC-α不介导血管抑素对创面愈合及血管增生的抑制作用。3.蛋白激酶C活化剂PMA促进创面愈合,而抑制剂Go6983延迟创面愈合。
Objective To research the roles of PKC-a in recombinant human angiostatin(K1-3) inhibition on wound healing and angiogenesis in the ventral skin of rabbit ears.
Methods The wound healing model was built on the ventral skin of rabbit ears.The wounds were respectively treaed with PBS, recombinant human angiostatin, PMA, G56983, recombinant human angiostatin combined with PMA or Go6983once a day until epithelization(13-16days).Wound images were collected to calculate wound healing rates with Image-Pro Plus6.0software on3d,7d and11d.And wound healing time was recorded.Microvessel density(MVD) and the expression of PKC-α in wound healing process was detected by immunohistochemical staining with vascular endothelial cell-specific marker CD34and PKC-α polyclonal antibody.The wound healing time, the wound healing rates, the MVD and the expression of PKC-α were expressed with Mean±tandard difference (x±s),which were assessed by one-way ANOVA when the homogeneity of variance between groups and their further multiple comparison by LSD(least significant different) method, using the Kruskal-Wallis Test when heterogeneity of variance.
Results1.The wound healing time in rh-AS group and Go6983group was longer than control group but PMA group was shortened compared with control group(P＜0.05).The wound healing time in rh-AS group was longer than rh-AS+PMA group,but shorter compared with rh-AS+Go6983group(P＜0.05).The wound healing time in PMA group was shorter in rh-AS+PMA group(P＜0.05).And the wound healing time in Go6983group was shorter compared with rh-AS+Go6983group(P＜0.05).
2.There were differences on wound healing rates in every group at different time:Wound healing time on the3rd day after injury in every group was no significant difference(P＞0.05).On the7th and11th day after injury,the wound healing rates in rh-AS group and Go6983group were lower than control group,but PMA group was higher than control group(P＜0.05).Rh-AS group had lower wound healing rates than rh-AS+PMA group,and higher compared with rh-AS+Go6983group(P＜0.05).The wound healing rates in PMA group and Go6983group was higher than in rh-AS+PMA group and rh-AS+Go6983group,respectively(P＜0.05).
3.Microvessel density:The microvessel density of rh-AS group, Go6983group and rh-AS+Go6983group was lower than control group on the any day after injury (P<0.05) whereas that of PMA group was higher than the other groups(P＜0.05). The microvessel density in every group declined with the wound epithelialization, but that in PMA group was higher than other groups(P＜0.05).
4.The expression levels of PKC-α:PKC-α was widely expressed in all kinds of cells the wound such as fibroblasts,endothelial cells,epidermal cells. The expression of PKC-a and the proportion of positive cells(fibroblasts,endothelial cells,epidermal cells) increased in every group with the wound healing progress.On the same time, the expression levels of PKC-a in rh-AS group was no significant difference with control group(P＞0.05).The proportion of positive cells in PMA group or rh-AS+PMA group was higher than control group and rh-AS group.The expression levels of PKC-a in Go6983group and rh-AS+Go6983group was lower compared with control group or rh-AS group(P＜0.05).
Conclusions1. The angiostatin might inhibit the angiogenesis in the wound healing and delays wound healing.
2. PKC-a might not mediate the inhibition effects of angiostatin on the wound healing and angiogenesis.
3. PMA might be conducive to the wound healing whereas Go6983might delay wound healing.
方法构建兔耳腹侧皮肤创面愈合模型。创面分别给予PBS液(对照组)、rh-AS(K1-3)(rh-AS组)、PMA (PMA组)、Go6983(Go6983组)、rh-AS联合PMA (rh-AS+PMA组)和rh-AS联合Go6983(rh-AS+Go6983组)湿敷,每日1次,连续13-16天(上皮化)。分别于伤后3天、7天、11天,采集创面图像,用Image-Pro Plus6.0图像处理软件计算创面愈合率,并记录各组创面愈合时间。于伤后第3天、7天、11天、上皮化时切取创面标本,采用CD34免疫组化染色检测微血管密度变化,用免疫组化方法半定量检测各时间点创面组织中PKC-a表达情况。创面愈合时间、创面愈合率、微血管密度及PKC-a阳性细胞比例均采用单因素方差分析,组间两两比较采用LSD法检验,若方差不齐则采用Kruskal-Wallis检验；P<0.05表示差异有统计学意义。
结果1rh-AS组和G66983组创面愈合时间长于对照组而PMA组创面愈合时间短于对照组(P<0.05)；rh-AS组创面愈合时间长于rh-AS+PMA组,但较rh-AS+Go6983组缩短(P<0.05)；PMA组创面愈合时间短于rh-AS+PMA组(P<0.05)；G66983组创面愈合时间较rh-AS+Go6983组缩短(P<0.05)。
2.伤后第3天各组间创面愈合率无差异(P>0.05)。伤后第7天：rh-AS组、G66983组创面愈合率小于对照组,而PMA组则高于对照组(P＜0.05); rh-AS组创面愈合率低于rh-AS+PMA组,而高于rh-AS+Go6983组(P＜0.05); PMA组创面愈合率高于rh-AS+PMA组(P<0.05)；G66983组创面愈合率高于rh-AS+Go6983组(P<0.05)。伤后第11天：rh-AS组、G66983组创面愈合率低于对照组(P<0.05),PMA组高于对照组(P<0.05)；rh-AS组创面愈合率高于rh-AS+Go6983组(P<0.05)；PMA组创面愈合率高于rh-AS+PMA组(P<0.05)；Go6983组创面愈合率高于rh-AS+Go6983组(P<0.05)。
3.微血管密度测定：伤后3天、7天、11天各组创面比较,rh-AS组、G66983组、rh-AS+PMA组、rh-AS+Go6983组微血管密度小于对照组(P<0.05),PMA组血管增生显著高于对照组及其余各组(P<0.05)。各组创面上皮化时,新生血管也随之退化：各组微血管密度下降,但PMA组微血管密度仍高于各组(P<0.05)。
4.PKC-α广泛表达于创面组织细胞,随创面愈合过程进展,各组PKC-α表达增强,阳性细胞(成纤维细胞、内皮细胞、表皮细胞)比例增加。同一时间点组间比较,rh-AS组PKC-α表达水平与对照组无差异(P>0.05),PMA组、rh-AS+PMA组各时间点PKC-α阳性细胞比例均高于对照组和rh-AS组,Go6983组、rh-AS+Go6983组低于对照组和rh-AS组(P<0.05)。
结论1.血管抑素抑制创面愈合过程中血管增生,延迟创面愈合。2. PKC-α不介导血管抑素对创面愈合及血管增生的抑制作用。3.蛋白激酶C活化剂PMA促进创面愈合,而抑制剂Go6983延迟创面愈合。
Objective To research the roles of PKC-a in recombinant human angiostatin(K1-3) inhibition on wound healing and angiogenesis in the ventral skin of rabbit ears.
Methods The wound healing model was built on the ventral skin of rabbit ears.The wounds were respectively treaed with PBS, recombinant human angiostatin, PMA, G56983, recombinant human angiostatin combined with PMA or Go6983once a day until epithelization(13-16days).Wound images were collected to calculate wound healing rates with Image-Pro Plus6.0software on3d,7d and11d.And wound healing time was recorded.Microvessel density(MVD) and the expression of PKC-α in wound healing process was detected by immunohistochemical staining with vascular endothelial cell-specific marker CD34and PKC-α polyclonal antibody.The wound healing time, the wound healing rates, the MVD and the expression of PKC-α were expressed with Mean±tandard difference (x±s),which were assessed by one-way ANOVA when the homogeneity of variance between groups and their further multiple comparison by LSD(least significant different) method, using the Kruskal-Wallis Test when heterogeneity of variance.
Results1.The wound healing time in rh-AS group and Go6983group was longer than control group but PMA group was shortened compared with control group(P＜0.05).The wound healing time in rh-AS group was longer than rh-AS+PMA group,but shorter compared with rh-AS+Go6983group(P＜0.05).The wound healing time in PMA group was shorter in rh-AS+PMA group(P＜0.05).And the wound healing time in Go6983group was shorter compared with rh-AS+Go6983group(P＜0.05).
2.There were differences on wound healing rates in every group at different time:Wound healing time on the3rd day after injury in every group was no significant difference(P＞0.05).On the7th and11th day after injury,the wound healing rates in rh-AS group and Go6983group were lower than control group,but PMA group was higher than control group(P＜0.05).Rh-AS group had lower wound healing rates than rh-AS+PMA group,and higher compared with rh-AS+Go6983group(P＜0.05).The wound healing rates in PMA group and Go6983group was higher than in rh-AS+PMA group and rh-AS+Go6983group,respectively(P＜0.05).
3.Microvessel density:The microvessel density of rh-AS group, Go6983group and rh-AS+Go6983group was lower than control group on the any day after injury (P<0.05) whereas that of PMA group was higher than the other groups(P＜0.05). The microvessel density in every group declined with the wound epithelialization, but that in PMA group was higher than other groups(P＜0.05).
4.The expression levels of PKC-α:PKC-α was widely expressed in all kinds of cells the wound such as fibroblasts,endothelial cells,epidermal cells. The expression of PKC-a and the proportion of positive cells(fibroblasts,endothelial cells,epidermal cells) increased in every group with the wound healing progress.On the same time, the expression levels of PKC-a in rh-AS group was no significant difference with control group(P＞0.05).The proportion of positive cells in PMA group or rh-AS+PMA group was higher than control group and rh-AS group.The expression levels of PKC-a in Go6983group and rh-AS+Go6983group was lower compared with control group or rh-AS group(P＜0.05).
Conclusions1. The angiostatin might inhibit the angiogenesis in the wound healing and delays wound healing.
2. PKC-a might not mediate the inhibition effects of angiostatin on the wound healing and angiogenesis.
3. PMA might be conducive to the wound healing whereas Go6983might delay wound healing.
引文
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[50].Eming SA,Brachvogel B,Odorisio T,Koch M.Regulation of angiogenesis:wound healing as a model[J].Prog Histochem Cytochem.2007,42(3):115-70.
[51]. Zhang XF,Guo SZ,Lu KH,Li HY,Li XD,Zhang LX,Yang L.Different roles of PKC and PKA in effect of interferon-y on proliferation and collagen synthesis of fibroblasts[J].Acta Pharmacol Sinica.2004,25:1320-6.
[52]. Fu X,Shen Z,Chen Y,Xie J,Guo Z,Zhang M,Sheng Z.Randomised placebo-controlled trial of use of topical recombinant bovine basic fibroblast growth factor for second-degree burns[J]. Lancet.1998,352 (9141):1661-4.
[53].Schlessinger J.Cell signaling by receptor tyrosine kinases[J].Cell.2000,103(2):211-25.
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[55].Young TA,Wang H,Munk S,Hammoudi DS,Young DS,Mandelcorn MS,Whiteside CI.Vascular endothelial growth factor expression and secretion by retinal pigment epithelial cells in high glucose and hypoxia is protein kinase C-dependent[J].Experimental Eye Research.2005,80(5):651-62.
[56].Bokhari SM,Zhou L,Karasek MA,Paturi SG.Chaudhuri V.Regulation of skin microvasculature angiogenesis,cell migration,and permeability by a specific inhibitor of PKC alpha[J].J Invest Dermatol.2006,126(2):460-7.
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1. Folkman J.Angiogenesis.Annu Rev Med,2006,57:1-18.
2. Bdolah Y,Sukhatme VP,Karumanchi SA.Angiogenic imbalance in the pathophysiology of preeclampsia:newer insights. Semin Nephrol[J],2004,24:548-56.
3. Sakural T, Kudo M. Signaling pathways governing tumor angiogenesis. Oncology,2011, 81(suppl 1):24-9.
4. O'Reilly MS,Holmgren L,Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J.Angiostatin:a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.Cell,1994,79(2):315-28.
5. Chang PC,Wu HL,Lin HC,Wang KC,Shi GY.Human plasminogen kringle 1-5 reduces atherosclerosis neointinma formation in mice by suppressing the inflammatory signaling pathway[J].J Hhromb Haemost,2010,8(1):194-201.
6. Nick R. An Inhibitor of the F1 Subunit of ATP Synthase(IF1) Modulates the Activity of Angiostatin on the Endothelial Cell Surface[J]. J Biol Chem,2005,280(3):1740-5.
7. Yamamoto K,Shimizu N,Obi S,Kumagaya S,Taketani Y, Kamiya A, Ando J.Involvement of cell surface ATP synthase in flow-induced ATP release by vascular endothelial cells[J]. Am J Physiol Heart Circ Physiol,2007,293(3):1646-53.
8. Wahl ML,Kenan DJ,Gonzalez-Gronow M,Pizzo SV.Angiostatin's molecular mechanism:aspects of specificity and regulation elucidated[J].J Cell Biochem,2005,96(2):242-61.
9. Chi SL,Pizzo SV.Angiostatin is directly cytotoxic to tumor cells at low extracellular pH:a mechanism dependent on cell surface-associated ATP synthase. Cancer Research,2006, 66(2):875-82.
10. Moser T L,Kenan D J,Ashley TA, Roy JA, Goodman MD, Misra UK, Cheek DJ, Pizzo SV.Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin [J]. ProcNatl AcadSci USA,2001,98 (12):6656-61.
11. Moser T L,Stack M S,Asplin I, Enghild JJ, Hojrup P, Everitt L, Hubchak S, Schnaper HW, Pizzo SV.Angiostatin binds ATP synthase on the surface of human endothelial cells[J]. ProcNatl Acad Sci USA,2004,96(6):2811-6.
12. Chi SL,Wanhl ML,Mowery YM, Shan S, Mukhopadhyay S, Hilderbrand SC, Kenan DJ, Lipes BD, Johnson CE, Marusich MF, Capaldi RA, Dewhirst MW, Pizzo SV.Angiostatin-Like Activity of a Monoclonal Antibody to the Catalytic Subunit of FIFO ATP Synthase[J].Cancer Res,2007,68(10):4716-24.
13. Meghan C B,Izabela S,Luis D V, Tuszynski GP, Marcinkiewicz C. Angiostatic activity of obtustatin as α1β1 integrin inhibitor in experimental melanoma growth[J].Int J Cancer, 2008,123(9):2195-203.
14. Heissig B,Ohki-Koizumi M,Tashiro Y, Gritli I, Sato-Kusubata K, Hattori K. New functions of the fibrinolytic system in bone marrow cell-derived angiogenesis[J].Int J Hematol,2012,95(2):131-7.
15. Pozzi A, Moberg PE, Miles LA,Wagner S, Soloway P, Gardner HA.Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization[J].ProcNatlAcadSci USA,2000,97(5):2202-7.
16.张玲.血管抑素对肺癌生物学行为的影响及抑制肿瘤血管形成分子机制的研究[J].中国医科大学博士学位论文,2008：1-73.
17. Chang PC, Chang YJ, Wu HL, Chang CW, Lin CI, Wang WC, Shi GY. Mutation of human plasminogen kringle 1-5 enhances anti-angiogenic action via increased interaction with integrin alpha(v)beta(3)[J]. Thromb Haemost,2008,99(4):729-38.
18. Tarui T, Majumdar M, Miles LA, Ruf W, Takada Y. Plasmin-induced migration of endothelial cells:apotential target for the anti-angiog enicaction of angiostatin[J].J Biol Chem, 2002,277(37):33564-70.
19. Claesson-Welsh L, Welsh M, Ito N, Anand-Apte B, Soker S, Zetter B, O'Reilly M, Folkman J.Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrinbinding motif RGD[J].ProcNatlAcad Sci USA,1998,95(10):5579-83.
20. Troyanovsky B, Levchenko T, Mansson G, Matvijenko O, Holmgren L. Angiomotin: anangiostatin binding protein that regulates endothelial cell migration and tube formation [J].J Cell Biol,2001,152(6):1247-54.
21. Karin Aase, Mira Ernkvist, Lwaki Ebarasi, Jakobsson L, Majumdar A, Yi C, Birot O, Ming Y, Kvanta A, Edholm D, Aspenstrom P, Kissil J, Claesson-Welsh L, Shimono A, Holmgren L.Angiomotin regulates endothelial cell migration during embryonic angiogenesis[J].Genes Dev,2007,21:2055-68.
22. Gagne V, Moreau J, Plourde M, Lapointe M, Lord M, Gagnon E, Fernandes MJ. Human angiomotin-like I associates with an angiomotin protein complex through its coiled-coil domain and induces the remodeling of the actin cytoskeleton[J].Cell Motil Cytoskeleton,2009, 66(9):754-68.
23. Levchenko T, Aase K, Troyanovsky B, Bratt A, Holmgren L. Loss of responsiveness to chemotactic factors by deletion of the C-terminal protein interaction site of angiomotin[J].J Cell Sci,2003,116:3803-10.
24. Takahashi S, Shinya T, Sugiyama A. Angiostatin Inhibition of Vascular Endothelial Growth Factor-Stimulated Nitric Oxide Production in Endothelial Cells[J]. Journal of Pharmacological Sciences,2010,112(4):432-7.
25. Zhu M, Bi X, Jia Q, Shangguan S.The possible mechanism for impaired angiogenesis after transient focal ischemia in type 2 diabetic GK rats:different expressions of angiostatin and vascular endothelial growth factor[J]. Biomed Pharmacother,2010,64(3):208-13.
26. Yang H,Xu Z,luvone PM,Grossniklaus HE.Angiostatin decreases cell migration and vascular endothelium growth factor(VEGF)to pigment epithelium derived factor(PEDF)RNAratio in vitro and in a murine ocular melanomamodel[J]. Mol Vis,2006,22(12):511-7.
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[8]. Wahl ML,Kenan DJ,Gonzalez GM,Pizzo SV.Angiostatin's molecular mechanism:aspects of specificity and regulation elucidated[J].J Cell Biochem.2005,96(2):242-61.
[9]. Chi SL,Pizzo SV.Angiostatin is directly cytotoxic to tumor cells at low extracellular pH:a mechanism dependent on cell surface-associated ATP synthase[J].Cancer Research.2006, 66(2):875-82.
[10].Moser TL,Kenan DJ,Ashley TA,Roy JA,Goodman MD,Misra UK,Cheek DJ,Pizzo SV.Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin [J].ProcNatl AcadSci USA.2001,98(12):6656-61.
[11].Meghan CB,Izabela S,Luis DV,Tuszynski GP,Marcinkiewicz C.Angiostatic activity of obtustatin as α1β1 integrin inhibitor in experimental melanoma growth[J].Int J Cancer. 2008,123(9):2195-203.
[12].Chang PC,Chang YJ,Wu HL,Chang CW,Lin CI,Wang WC,Shi GY.Mutation of human plasminogen kringle 1-5 enhances anti-angiogenic action via increased interaction with integrin alpha(v)beta(3)[J].Thromb Haemost.2008,99(4):729-38.
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1. Folkman J.Angiogenesis.Annu Rev Med,2006,57:1-18.
2. Bdolah Y,Sukhatme VP,Karumanchi SA.Angiogenic imbalance in the pathophysiology of preeclampsia:newer insights. Semin Nephrol[J],2004,24:548-56.
3. Sakural T, Kudo M. Signaling pathways governing tumor angiogenesis. Oncology,2011, 81(suppl 1):24-9.
4. O'Reilly MS,Holmgren L,Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J.Angiostatin:a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.Cell,1994,79(2):315-28.
5. Chang PC,Wu HL,Lin HC,Wang KC,Shi GY.Human plasminogen kringle 1-5 reduces atherosclerosis neointinma formation in mice by suppressing the inflammatory signaling pathway[J].J Hhromb Haemost,2010,8(1):194-201.
6. Nick R. An Inhibitor of the F1 Subunit of ATP Synthase(IF1) Modulates the Activity of Angiostatin on the Endothelial Cell Surface[J]. J Biol Chem,2005,280(3):1740-5.
7. Yamamoto K,Shimizu N,Obi S,Kumagaya S,Taketani Y, Kamiya A, Ando J.Involvement of cell surface ATP synthase in flow-induced ATP release by vascular endothelial cells[J]. Am J Physiol Heart Circ Physiol,2007,293(3):1646-53.
8. Wahl ML,Kenan DJ,Gonzalez-Gronow M,Pizzo SV.Angiostatin's molecular mechanism:aspects of specificity and regulation elucidated[J].J Cell Biochem,2005,96(2):242-61.
9. Chi SL,Pizzo SV.Angiostatin is directly cytotoxic to tumor cells at low extracellular pH:a mechanism dependent on cell surface-associated ATP synthase. Cancer Research,2006, 66(2):875-82.
10. Moser T L,Kenan D J,Ashley TA, Roy JA, Goodman MD, Misra UK, Cheek DJ, Pizzo SV.Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin [J]. ProcNatl AcadSci USA,2001,98 (12):6656-61.
11. Moser T L,Stack M S,Asplin I, Enghild JJ, Hojrup P, Everitt L, Hubchak S, Schnaper HW, Pizzo SV.Angiostatin binds ATP synthase on the surface of human endothelial cells[J]. ProcNatl Acad Sci USA,2004,96(6):2811-6.
12. Chi SL,Wanhl ML,Mowery YM, Shan S, Mukhopadhyay S, Hilderbrand SC, Kenan DJ, Lipes BD, Johnson CE, Marusich MF, Capaldi RA, Dewhirst MW, Pizzo SV.Angiostatin-Like Activity of a Monoclonal Antibody to the Catalytic Subunit of FIFO ATP Synthase[J].Cancer Res,2007,68(10):4716-24.
13. Meghan C B,Izabela S,Luis D V, Tuszynski GP, Marcinkiewicz C. Angiostatic activity of obtustatin as α1β1 integrin inhibitor in experimental melanoma growth[J].Int J Cancer, 2008,123(9):2195-203.
14. Heissig B,Ohki-Koizumi M,Tashiro Y, Gritli I, Sato-Kusubata K, Hattori K. New functions of the fibrinolytic system in bone marrow cell-derived angiogenesis[J].Int J Hematol,2012,95(2):131-7.
15. Pozzi A, Moberg PE, Miles LA,Wagner S, Soloway P, Gardner HA.Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization[J].ProcNatlAcadSci USA,2000,97(5):2202-7.
16.张玲.血管抑素对肺癌生物学行为的影响及抑制肿瘤血管形成分子机制的研究[J].中国医科大学博士学位论文,2008：1-73.
17. Chang PC, Chang YJ, Wu HL, Chang CW, Lin CI, Wang WC, Shi GY. Mutation of human plasminogen kringle 1-5 enhances anti-angiogenic action via increased interaction with integrin alpha(v)beta(3)[J]. Thromb Haemost,2008,99(4):729-38.
18. Tarui T, Majumdar M, Miles LA, Ruf W, Takada Y. Plasmin-induced migration of endothelial cells:apotential target for the anti-angiog enicaction of angiostatin[J].J Biol Chem, 2002,277(37):33564-70.
19. Claesson-Welsh L, Welsh M, Ito N, Anand-Apte B, Soker S, Zetter B, O'Reilly M, Folkman J.Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrinbinding motif RGD[J].ProcNatlAcad Sci USA,1998,95(10):5579-83.
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