Abstract
Angiogenesis, the process of new microvessel development, is encountered in a select number of physiological processes and is central to the pathogenesis of a wide variety of diseases. There is now convincing evidence that regulated patterns of endothelial cell survival and death, a process known as apoptosis, play a central role in the periodic remodeling of the vasculature, and in the timely evolution and regression of angiogenic responses. In this review we discuss the current evidence suggesting a role for inducers and inhibitors of angiogenesis as well as other mediators that modify endothelial cells functions in the survival and death of endothelial cells. We also discuss how dysregulation of apoptosis can lead to aberrant angiogenesis as demonstrated in the pathogenesis of retinopathy of prematurity and cancer.
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Vaux DL, Korsmeyer SJ. Cell death in development. Cell 1999; 96: 245–54.
Wyllie AH. Apoptosis and the regulation of cell numbers in normal and neoplastic tissues: An overview. Cancer Metastasis Rev 1992; 11: 95–103.
Green DR. Apoptotic pathways: The roads to ruin. Cell 1998; 94: 695–8.
Vogt C. Untersuchungen über die Entwicklungsgeschichte der Geburtsshelferkroete (Alytes obstertricians). Solothurn, Switzerland: Jent und Gassman 1842.
Kerr JFR, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239–57.
Greenhalgh DG. The role of apoptosis in wound healing. Int J Biochem Cell Biol 1998; 30: 1019–30.
Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267: 1456–62.
Metcalf D, Linderman GF, Nicola NA. Analysis of hematopoiesis in max 41 transgenic mice that exhibit sustained elevations of blood granulocytes and monocytes. Blood 1995; 85: 2364–70.
Raff M. Cell suicide for beginners. Nature 1998; 396: 119–22.
Levine B. Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene. Nature 1993; 361: 739–42.
Ameisen JC. The origin of programmed cell death. Science 1996; 272: 1278–9.
Steller H. Mechanisms and genes of cellular suicide. Science 1995; 267: 1445–9.
Ellis RE, Yuan J, Horvitz HR. Mechanisms and functions of cell death. Annu Rev Cell Biol 1991; 7: 663–98.
Metzstein MM, Stanfield GM, Horvitz HR. Genetics of programmed cell death in C. elegans past, present and future. Trends Genetics 1998; 14: 410–6.
Sulston JE, Horvitz HR. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 1977; 56: 110–56.
Wu DY, Wallen HD, Nuñez G. Interaction and regulation of subcellular localization of CED-4 by CED-9. Science 1997; 275: 1126–9.
Chinnaiyan AM, O'Rourke K, Lane BR, Dixit VM. Interaction of CED-4 with CED-3 and CED-9 — a molecular framework for cell death. Science 1997; 275: 1122–6.
Spector MS, Desnoyers S, Hoeppner DJ, Hengartner MO. Interaction between the C. elegans cell death regulators Ced-9 and Ced-4. Nature 1997; 385: 653–6.
Del Peso L, Gonzalez VM, Nuñez G. Caenorhabditis elegans EGL-1 disrupts the interaction of CED-9 with CED-4 and promotes CED-3 activation. J Biol Chem 1998; 273: 33495–500.
Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol 1994; 124: 1–6.
Chao DT, Korsmeyer SJ. BCL-2 family: Regulators of cell death. Ann Rev Imm 1998; 16: 395–419.
Reed JC. Bcl-2 family proteins. Oncogene 1998; 17: 3225–36.
Reed JC. Double identity for proteins of the Bcl-2 family. Nature 1997; 387: 773–6.
Wang K, Yin XM, Chao DT et al. BID: A novel BH3 domain-only death agonist. Genes Dev 1996; 10: 2859–69.
Thonberry NA, Lazebnik Y. Caspases: Enemies within. Science 1998; 281: 1312–6.
Zou H, Henzel WJ, Liu X et al. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 1997; 90: 405–13.
Pan G, O'Rourke K, Dixit VM. Caspase-9, Bcl-xL, and Apaf-1 form a ternary complex. J Biol Chem 1998; 273: 5841–5.
Hu Y, Benedict MA, Wu D et al. Bcl-xL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc Natl Acad Sci USA 1998a; 95: 4386–91.
Hu Y, Ding L, Spencer DM, Nuñez G. WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation. J Biol Chem 1998(b); 273: 33489–94.
Srinivassula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES. Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Mol Cell 1998; 1: 949–57.
Nuñez G, Benedict MA, Hu Y, Inohara N. Caspases: The proteases of the apoptotic pathway. Oncogene 1998; 17: 3237–45.
Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309–12.
Li P, Nijhawan D, Budihardjo I et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479–89.
Cardone MH, Roy N, Stennicke HR et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282: 1318–21.
Faleiro L, Kobayashi R, Fearnhead H, Lazebnik Y. Multiple species of CPP32 and Mch2 are the major active caspases present in apoptotic cells. EMBO J 1997; 16: 2271–81.
Enari M, Sakahira H, Yokoyama H et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 1998; 391: 43–50.
Sakahira H, Enari M, Nagata S. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 1998; 391: 96–9.
Mukae N, Enari M, Sakahira H et al. Molecular cloning and characterization of human caspase-activated DNase. Proc Natl Acad Sci USA 1998; 95: 9123–8.
Ashkenazi A, Dixit VM. Death receptors: Signaling and modulation. Science 1998; 281: 1305–8.
Smith CA, Farrah T, Goodwin RG. The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death. Cell 1994; 76: 959–62.
Tartaglia LA, Ayres TM, Wong GH, Goeddel DV. A novel domain within the 55 kd TNF receptor signals cell death. Cell 1993; 74: 845–53.
Medema JP, Scaffidi C, Kischkel FC et al. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 1997; 16: 2794–804.
Yang X, Chang HY, Baltimore D. Autoproteolytic activation of pro-caspases by oligomerization. Mol Cell 1998; 1: 319–25.
MacCorkle RA, Freeman KW, Spencer DM. Synthetic activation of caspases: Artificial death switches. Proc Natl Acad Sci USA 1998; 95: 3655–60.
Stennicke HR, Jurgensmeier JM, Shin H et al. Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem 1998; 273: 27084–90.
Muzio M, Chinnaiyan AM, Kischkel FC et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 1996; 85: 817–27.
Boise LH, Thompson CB. Bcl-x(L) can inhibit apoptosis in cells that have undergone Fas-induced protease activation. Proc Natl Acad Sci USA 1997; 94: 3759–64.
Cursio R, Gugenheim J, Ricci JE et al. A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis. FASEB J 1999; 13: 253–61.
Schierle GS, Hansson O, Leist M et al. Caspase inhibition reduces apoptosis and increases survival of nigral transplants. Nat Med 1999; 5: 97–100.
Thornberry NA. Caspases: key mediators of apoptosis. Chem Biol 1998; 5: R97–103.
Adams JM, Cory S. The Bcl-2 protein family: Arbiters of cell survival. Science 1998; 281: 1322–6.
Monney L, Otter I, Olivier R et al. Defects in the ubiquitin pathway induce caspase-independent apoptosis blocked by Bcl-2. J Biol Chem 1998; 273: 6121–31.
Gross A, Jockel J, Wei MC, Korsmeyer SJ. Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J 1998; 17: 3878–85.
Risau W, Flamme I. Vasculogenesis. Annu. Rev. Cell Dev. Biol. 1997; 11: 73–91.
Risau W. Mechanisms of angiogenesis. Nature 1997; 386: 671–4.
Ferrara N, Carver-Moore K, Chen H et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380: 439–42.
Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the flt-1 tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995; 376: 66–70.
Hertig AT. Contrib Embryol 1935; 25: 37.
Asahara T, Murohara T, Sullivan A et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964–7.
Denekamp J. Progress in applied microcirculation In Hammersen F, Hudlicka O (eds): Perspectives in Methodology for Studies of the Microcirculation. Basel: Karger 1984; 42: 28–38.
Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992; 267: 10931–4.
Gross JL, Moscatelli D, Rifkin DB. Increased capillary endothelial cell protease activity in response to angiogenic stimuli in vitro. Proc Natl Acad Sci USA 1983; 80: 2623–727.
Folkman J, Haudenschild C. Angiogenesis in vitro. Nature 1980; 288: 551–6.
Nicosia RF, Villaschi S. Rat aortic smooth muscle cells become perycites during angiogenesis in vitro. Lab Invest 1995; 73: 658–66.
Folkman J. What is the role of endothelial cells in angiogenesis? Lab Invest 1984; 51: 601–4.
Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998; 125: 1591–8.
Polverini PJ. The pathophysiology of angiogenesis. Crit Rev Oral Biol Med 1995; 6: 230–47.
Lawler J. The structural and functional properties of thrombospondin. Blood 1986; 67: 1197–209.
Dardik R, Lahav J. The structure of endothelial cell thrombospondin. Characterization of the heparin-binding domains. Eur J Biochem 1987; 168: 347–55.
Bornstein P. Diversity of function is inherited in matricellular proteins: An appraisal of thrombospondin-1. J Cell Biol 1995; 130: 503–6.
Good DJ, Polverini PJ, Rastinejad F et al. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci USA 1990; 87: 6624–8.
Tolsma SS, Volpert VO, Good DJ et al. Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity. J Cell Biol 1993; 122: 497–511.
DiPietro LA, Nissen NN, Gamelli RL et al. Thrombospondin 1 synthesis and function in wound repair. Am J Pathol 1996; 148: 1851–60.
O'Shea KS, Dixit VM. Unique distribution of the extracellular matrix component thrombospondin in the developing mouse embryo. J Cell Biol 1988; 107: 2737–48.
Iruela-Arispe ML, Porter P, Bornstein P, Sage EH. Thrombospondin-1, an inhibitor of angiogenesis, is regulated by progesterone in the human endometrium. J Clin Invest 1996; 97: 403–12.
Iruela-Arispe ML, Bornstein P, Sage H. Thrombospondin exerts an antiangiogenic effect on cord formation by endothelial cells in vitro. Proc Natl Acad Sci USA 1991; 88: 5026–30.
Lahav J. The functions of thrombospondin and its involvement in physiology and pathophysiology. Biochim Biophys Acta 1993; 1182: 1–14.
Bornstein P, Sage EH. Thrombospondins. Methods Enzymol 1994; 245: 62–85.
Adams JC. Thrombospondin-1. Int J Biochem Cell Biol. 1997; 29: 861–5.
Bagavandoss P, Wilks JW. Specific inhibition of endothelial cell proliferation by thrombospondin. Biochem Biophys Res Commun 1990; 170: 867–72.
Taraboletti G, Roberts D, Liotta LA, Giavazzi R. Platelet thrombospondin modulates endothelial cell adhesion, motility, and growth: A potential angiogenesis regulatory factor. J Cell Biol 1990; 111: 765–72.
DiPietro LA, Nebgen DR, Polverini PJ. Downregulation of endothelial cell thrombospondin 1 enhances in vitro angiogenesis. J Vasc Res 1994; 31: 178–85.
Panetti TS, Chen H, Misenheimer TM et al. Endothelial cell mitogenesis induced by LPA: Inhibition by thrombospondin-1 and thrombospondin-2. J Lab Clin Med 1997; 129: 208–16.
Bagavandoss P, Kaytes P, Vogeli G et al. Recombinant truncated thrombospondin-1 monomer modulates endothelial cell plasminogen activator inhibitor 1 accumulation and proliferation in vitro. Biochem Biophys Res Commun 1993; 192: 325–32.
Canfield AE, Schor AM. Evidence that tenascin and thrombospondin-1 modulate sprouting of endothelial cells. J Cell Sci 1995; 108: 797–809.
Vogel T, Guo NH, Krutzsch HC et al. Modulation of endothelial cell proliferation, adhesion, and motility by recombinant heparin-binding domain and synthetic peptides from the type I repeats of thrombospondin. J Cell Biochem 1993; 53: 74–84.
Prochownik EV, O'Rourke K, Dixit VM. Expression and analysis of COOH-terminal deletions of the human thrombospondin molecule. J Cell Biol 1989; 109: 843–52.
Castle VP, Dixit VM, Polverini PJ. Thrombospondin-1 suppresses tumorigenesis and angiogenesis in serum-and anchorage-independent NIH 3T3 cells. Lab Invest 1997; 77: 51–61.
Dawson DW, Pearce SF, Zhong R et al. CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells. J Cell Biol 1997; 138: 707–17.
Guo N, Krutzsch HC, Inman JK, Roberts DD. Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells. Cancer Res 1997; 57: 1735–42.
O'Reilly MS, Holmgren L, Shing Y et al. Angiostatin: A circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harb Symp Quant Biol 1994a; 59: 471–82.
O'Reilly MS, Holmgren L, Shing Y et al. Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994b; 79: 315–28.
O'Reilly MS. Angiostatin: An endogenous inhibitor of angiogenesis and of tumor growth. EXS 1997; 79: 273–94.
Cao Y, Ji RW, Davidson D et al. Kringle domains of human angiostatin. Characterization of the anti-proliferative activity on endothelial cells. J Biol Chem 1996; 271: 29461–7.
Dong Z, Kumar R, Yang X, Fidler IJ. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 1997; 88: 801–10.
Patterson BC, Sang QA. Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J Biol Chem 1997; 272: 28823–5.
Lijnen HR, Ugwu F, Bini A, Collen D. Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP-3). Biochemistry 1998; 37: 4699–702.
Claesson-Welsh L, Welsh M, Ito N et al. Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc Natl Acad Sci USA 1998; 95: 5579–83.
Lucas R, Holmgren L, Garcia I et al. Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood 1998; 92: 4730–41.
Matthews N. Tumour-necrosis factor from the rabbit. II. Production by monocytes. Br J Cancer 1978; 38: 310–5.
Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Biol 1993a; 9: 317–43.
Diez-Roux G, Lang RA. Macrophages induce apoptosis in normal cells in vivo. Development 1997; 124: 3633–8.
Steffen M, Ottmann OG, Moore MA. Simultaneous production of tumor necrosis factor-alpha and lymphotoxin by normal T cells after induction with IL-2 and anti-T3. J Immunol 1988; 140: 2621–4.
Tracey KJ, Cerami A. Tumor necrosis factor: An updated review of its biology. Crit Care Med 1993b; 10: S415–22.
Robaye B, Mosselmans R, Fiers W et al. Tumor necrosis factor induces apoptosis (programmed cell death) in normal endothelial cells in vitro. Am J Pathol 1991; 138: 447–53.
Wendt CH, Polunovsky VA, Peterson MS et al. Alveolar epithelial cells regulate the induction of endothelial cell apoptosis. Am J Physiol 1994; 267: C893–900.
Polunovsky VA, Wendt CH, Ingbar DH et al. Induction of endothelial cell apoptosis by TNF alpha: Modulation by inhibitors of protein synthesis. Exp Cell Res 1994; 214: 584–94.
Pober JS. Activation and injury of endothelial cells by cytokines. Pathol Biol 1998; 46:159–63.
Marino MW, Dunbar JD, Wu LW et al. Inhibition of tumor necrosis factor signal transduction in endothelial cells by dimethylaminopurine. J Biol Chem 1996; 271: 28624–9.
Karsan A, Yee E, Harlan JM. Endothelial cell death induced by tumor necrosis factor-alpha is inhibited by the Bcl-2 family member, A1. J Biol Chem 1996; 271: 27201–4.
Badrichani AZ, Stroka DM, Bilbao G et al. Bcl-2 and Bcl-XL serve an anti-inflammatory function in endothelial cells through inhibition of NF-kappaB. J Clin Invest 1999; 103: 543–53.
Read MA, Whitley MZ, Williams AJ, Collins T. NF-kappa B and I kappa B alpha: An inducible regulatory system in endothelial activation. J Exp Med 1994; 179: 503–12.
Collins T, Read MA, Neish AS et al. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 1995; 9: 899–909.
Lakshminarayanan V, Drab-Weiss EA, Roebuck KA. H2O2 and tumor necrosis factor-alpha induce differential binding of the redox-responsive transcription factors AP-1 and NF-kappaB to the interleukin-8 promoter in endothelial and epithelial cells. J Biol Chem 1998; 273: 32670–8.
Yoshida S, Ono M, Shono T et al. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Mol Cell Biol 1997; 17: 4015–23.
Giraudo E, Primo L, Audero E et al. Tumor necrosis factor-alpha regulates expression of vascular endothelial growth factor receptor-2 and of its co-receptor neuropilin-1 in human vascular endothelial cells. J Biol Chem 1998; 273: 22128–35.
Obeid LM, Linardic CM, Karolak LA, Hannun YA. Programmed cell death induced by ceramide. Science 1993; 259: 1769–71.
Leibovich SJ, Polverini PJ, Shepard HM et al. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature 1987; 329: 630–2.
Frater-Schroder M, Risau W, Hallmann R et al. Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Natl Acad Sci USA 1987; 84: 5277–81.
Ryuto M, Ono M, Izumi H et al. Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1. J Biol Chem 1996; 271: 28220–8.
Tsukada T, Eguchi K, Migita K et al. Transforming growth factor beta 1 induces apoptotic cell death in cultured human umbilical vein endothelial cells with down-regulated expression of bcl-2. Biochem Biophys Res Commun 1995; 210: 1076–82.
Choi ME, Ballerman BJ. Inhibition of capillary morphogenesis and associated apoptosis by dominant negative mutant transforming growth factor-β receptors. J Biol Chem 1995; 270: 21144–50.
Brigham KL, Meyrick B. Endotoxin and lung injury. Am Rev Respir Dis 1986; 133: 913–27.
Hoyt DG, Mannix RJ, Rusnak JM et al. Collagen is a survival factor against LPS-induced apoptosis in cultured sheep pulmonary artery endothelial cells. Am J Physiol 1995; 269: L171–7.
Haimovitz-Friedman A, Cordon-Cardo C, Bayoumy S et al. Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation. J Exp Med 1997; 186: 1831–41.
Wong HR, Mannix RJ, Rusnak JM et al. The heat-shock response attenuates lipopolysaccharide-mediated apoptosis in cultured sheep pulmonary artery endothelial cells. Am J Respir Cell Mol Biol 1996; 15: 745–51.
Haendeler J, Zeiher AM, Dimmeler S. Vitamin C and E prevent lipopolysaccharide-induced apoptosis in human endothelial cells by modulation of Bcl-2 and Bax. Eur J Pharmacol 1996; 317: 407–11.
Maier JA, Morelli D, Balsari A. The differential response to interferon gamma by normal and transformed endothelial cells. Biochem Biophys Res Commun 1995; 214: 582–8.
Blanc EM, Toborek M, Mark RJ et al. Amyloid beta-peptide induces cell monolayer albumin permeability, impairs glucose transport, and induces apoptosis in vascular endothelial cells. J Neurochem 1997; 68: 1870–81.
Imai H, Werthessen NT, Taylor CB, Lee KT. Angiotoxicity and arteriosclerosis due to contaminants of USP-grade cholesterol. Arch Pathol Lab Med 1976; 100: 565–72.
Lizard G, Deckert V, Dubrez L et al. Induction of apoptosis in endothelial cells treated with cholesterol oxides. Am J Pathol 1996; 148: 1625–38.
Geng YJ, Libby P. Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme. Am J Pathol 1995; 147: 251–66.
Yeh CH, Peng HC, Huang TF. Accutin, a new disintegrin, inhibits angiogenesis in vitro and in vivo by acting as an integrin αvβ 3 antagonist and inducing apoptosis. Blood 1998; 92: 3268–76.
Polunovsky VA, Chen B, Henke C et al. Role of mesenchymal cell death in lung remodeling after injury. J Clin Invest 1993; 92: 388–97.
Dawicki DD, Chatterjee D, Wyche J, Rounds S. Extracellular ATP and adenosine cause apoptosis of pulmonary artery endothelial cells. Am J Physiol 1997; 273: L485–94.
Araki S, Tsuna I, Kaji K, Hayashi H. Programmed cell death in response to alkyllysophospholipids in endothelial cells. J Biochem 1994; 115: 245–7.
Yue TL, Wang X, Louden CS et al. 2-Methoxyestradiol, an endogenous estrogen metabolite, induces apoptosis in endothelial cells and inhibits angiogenesis: Possible role for stress-activated protein kinase signaling pathway and Fas expression. Mol Pharmacol 1997; 51: 951–62.
Lang R, Bishop MJ. Macrophages are required for cell death and tissue remodeling in the developing mouse eye. Cell 1993; 74: 453–62.
Lang RA, Lustig M, Francois F et al. Apoptosis during macrophage-dependent tissue remodelling. Development 1994; 120: 3395–403.
Meeson A, Palmer M, Calfon M, Lang RA. A relationship between flow and apoptosis during programmed capillary regression is revealed by vital analysis. Development 1996; 122: 3929–38.
Meeson AP, Argilla M, Witte L, Lang RA. VEGF deprivation-induced apoptosis is a component of programmed capillary regression. Development 1999; 126: 1407–15.
Senger DR, Galli SJ, Dvorak AM et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219: 983–5.
Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989; 161: 851–8.
Plöuet J, Schilling J, Gospodarowicz D. Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells. EMBO J 1989; 8: 3801–6.
Gospodarowicz D, Abraham JA, Schilling J. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci USA 1989; 86: 7311–5.
Ferrara N. Vascular endothelial growth factor. Eur J Cancer 1996; 32A: 2413–22.
Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999; 13: 9–22.
Nicosia RF, Nicosia SV, Smith M. Vascular endothelial growth factor, platelet-derived growth factor, and insulin-like growth factor-1 promote rat aortic angiogenesis in vitro. Am J Pathol 1994; 145: 1023–9.
Leung DW, Cachianes G, Kuang WJ et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 1306–9.
Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315: 1650–9.
Yoshida A, Anand-Apte B, Zetter BR. Differential endothelial migration and proliferation to basic fibroblast growth factor and vascular endothelial growth factor. Growth Factors 1996; 13: 57–64.
Melder RJ, Koenig GC, Witwer BP et al. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med 1996; 2: 992–7.
Spyridopoulos I, Brogi E, Kearney M et al. Vascular endothelial growth factor inhibits endothelial cell apoptosis induced by tumor necrosis factor-alpha: Balance between growth and death signals. J Mol Cell Cardiol 1997a; 29: 1321–30.
Meredith JE, Fazeli B, Schwartz MA. The extracellular matrix as a cell survival factor. Mol Cell Biol 1993; 4: 953–61.
Watanabe Y, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor inhibits anchorage-disruption-induced apoptosis in microvessel endothelial cells by inducing scaffold formation. Exp Cell Res 1997; 233: 340–9.
Gerber HP, Dixit V, Ferrara N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 1998a; 273: 13313–6.
Nör JE, Christensen J, Mooney DJ, Polverini PJ. Vascular Endothelial Growth Factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol 1999; 154: 375–84.
Kondo S, Yin D, Aoki T et al. bcl-2 gene prevents apoptosis of basic fibroblast growth factor-deprived murine aortic endothelial cells. Exp Cell Res 1994; 213: 428–32.
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. J Biol Chem 1998; 273: 30336–43.
Ilan N, Mahooti S, Madri JA. Distinct signal transduction pathways are utilized during the tube formation and survival phases of in vitro angiogenesis. J Cell Sci 1998; 111: 3621–31.
Maxwell PH, Dachs GU, Gleadle JM et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 1997; 94: 8104–9.
Ryan HE, Lo J, Johnson RS. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J 1998; 17: 3005–15.
Carmeliet P, Dor Y, Herbert J-M et al. Role of HIF-α in hypoxia-mediated apoptosis, cell proliferation, and tumor angiogenesis. Nature 1998; 394: 485–90.
Maxwell PH, Weisener MS, Chang G-W et al. The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399: 271–5.
Stebbins CE, Kaelin WG, Pavletich NP. Structure of the VHL-elonginC-elonginB complex: implications for VHL tumor suppressor function, Science 1999; 284: 455–61.
Kumura T, Koepp DM, Conrad MN et al. Rbx1, a conponent of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 1999; 284: 657–61.
Esch F, Baird A, Ling N et al. Primary structure of bovine pituitary basic fibroblast growth factor (FGF) and comparison with the amino-terminal sequence of bovine brain acidic FGF. Proc Natl Acad Sci USA 1985; 82: 6507–11.
Abraham JA, Mergia A, Whang JL et al. Nucleotide sequence of a bovine clone encoding the angiogenic protein, basic fibroblast growth factor. Science 1986; 233: 545–8.
Araki S, Shimada Y, Kaji K, Hayashi H. Apoptosis of vascular endothelial cells by fibroblast growth factor deprivation. Biochem Biophys Res Commun 1990a; 168: 1194–200.
Araki S, Simada Y, Kaji K, Hayashi H. Role of protein kinase C in the inhibition by fibroblast growth factor of apoptosis in serum-depleted endothelial cells. Biochem Biophys Res Commun 1990b; 172: 1081–5.
Fuks Z, Persaud RS, Alfieri A et al. Basic fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo. Cancer Res 1994; 54: 2582–90.
Langley RE, Bump EA, Quartuccio SG et al. Radiation-induced apoptosis in microvascular endothelial cells. Br J Cancer 1997; 75: 666–72.
Satake S, Kuzuya M, Ramos MA et al. Angiogenic stimuli are essential for survival of vascular endothelial cells in three-dimensional collagen lattice. Biochem Biophys Res Commun 1998; 244: 642–6.
Kondo S, Kondo Y, Yin D et al. Involvement of interleukin-1 beta-converting enzyme in apoptosis of bFGF-deprived murine aortic endothelial cells. FASEB J 1996; 10: 1192–7.
Karsan A, Yee E, Poirier GG et al. Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. Am J Pathol 1997; 151: 1775–84.
Brooks PC. Role of integrins in angiogenesis. Eur J Cancer 1996; 32A: 2423–9.
Brooks PC, Montgomery AM, Rosenfeld M et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994; 79: 1157–64.
Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 1994; 264: 569–71.
Stromblad S, Cheresh DA. Integrins, angiogenesis and vascular cell survival. Chem Biol 1996a; 3: 881–5.
Meredith J Jr, Mu Z, Saido T, Du X. Cleavage of the cytoplasmic domain of the integrin beta3 subunit during endothelial cell apoptosis. J Biol Chem 1998; 273: 19525–31.
Stromblad S, Becker JC, Yebra M et al. Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin α v β 3 during angiogenesis. J Clin Invest 1996b; 98: 426–33.
Scatena M, Almeida M, Chaisson ML et al. NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival. J Cell Biol 1998; 141: 1083–93.
Miao JY, Araki S, Hayashi H. Relationships between phosphatidylcholine-specific phospholipase C and integrins in cell-substratum adhesion and apoptosis in vascular endothelial cells. Endothelium 1997; 5: 297–305.
Ruegg C, Yilmaz A, Bieler G et al. Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med 1998; 4: 408–14.
Alonso J, Sanchez de Miguel L, Monton M et al. Endothelial cytosolic proteins bind to the 3′ untranslated region of endothelial nitric oxide synthase mRNA: Regulation by tumor necrosis factor alpha. Mol Cell Biol 1997; 17: 5719–26.
Lopez-Farre A, Rodriguez-Feo JA, Sanchez de Miguel L et al. Role of nitric oxide in the control of apoptosis in the microvasculature. Int J Biochem Cell Biol 1998; 30: 1095–106.
Lopez-Farre A, Sanchez de Miguel L, Caramelo C et al. Role of nitric oxide in autocrine control of growth and apoptosis of endothelial cells. Am J Physiol 1997; 272: H760–8.
Shimokawa H, Flavahan NA, Vanhoutte PM. Natural course of the impairment of endothelium-dependent relaxations after balloon endothelium removal in porcine coronary arteries. Possible dysfunction of a pertussis toxin-sensitive G protein. Circ Res 1989; 65: 740–53.
Alvarez RJ, Gips SJ, Moldovan N et al. 17β-estradiol inhibits apoptosis of endothelial cells. Biochem Biophys Res Commun 1997; 237: 372–81.
Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA 1991; 265: 1861–7.
Spyridopoulos I, Sullivan AB, Kearney M et al. Estrogen-receptor-mediated inhibition of human endothelial cell apoptosis. Estradiol as a survival factor. Circulation 1997b; 95: 1505–14.
Kato H, Shichiri M, Marumo F, Hirata Y. Adrenomedullin as an autocrine/paracrine apoptosis survival factor for rat endothelial cells. Endocrinology 1997; 138: 2615–20.
Zoellner H, Hofler M, Beckmann R et al. Serum albumin is a specific inhibitor of apoptosis in human endothelial cells. J Cell Sci 1996; 109: 2571–80.
Deveraux QL, Reed JC. IAP family of proteins-suppressors of apoptoisis. Genes Dev 1999; 13: 239–52.
Crook NE, Clem RJ, Miller LK. An apoptosis inhibiting baculovirus gene with a zinc finger-like motif. J Virol 1993; 67: 2168–74.
Birnbaum MJ, Clem RJ, Miller LK. An apoptosis inhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with Cys/His sequence motifs. J Virol 1994; 68: 2521–8.
Deveraux QL, Roy N, Stennicke HR et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 1998; 17: 2215–23.
Sandberg M, Vuorio T, Hirvonen H et al. Enhanced expression of TGF-beta and c-fos mRNAs in the growth plates of developing human long bones. Development 1988; 102: 461–70.
Roberts AB, Sporn MB, Assoian RK et al. Transforming growth factor type beta: Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 1986; 83: 4167–71.
Madri JA, Pratt BM, Tucker AM. Phenotypic modulation of endothelial cells by transforming growth factor-beta depends upon the composition and organization of the extracellular matrix. J Cell Biol 1988; 106: 1375–84.
Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 1994; 124: 619–26.
Benjamin LE, Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: Induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci USA 1997; 94: 8761–6.
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27–31.
Gibson DL, Sheps SB, Uh SH et al. Retinopathy of prematurity-induced blindness: Birth weight-specific survival and the new epidemic. Pediatrics 1990; 86: 405–12.
Ticho BH, Dreger V. Retinopathy of prematurity. Insight 1997; 22: 57–61.
Alon T, Hemo I, Itin A et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995; 1: 1024–8.
Stone J, Chan-Ling T, Pe'er J et al. Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity. Invest Ophthalmol Vis Sci 1996; 37: 290–9.
Penn JS, Tolman BL, Henry MM. Oxygen-induced retinopathy in the rat: relationship of retinal nonperfusion to subsequent neovascularization. Invest Ophthalmol Vis Sci 1994; 35: 3429–35.
Aiello LP, Northrup JM, Keyt BA et al. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 1995; 113: 1538–44.
Pierce EA, Foley ED, Smith LE. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 1996; 114: 1219–28.
Hebbandi SB, Bowen JR, Hipwell GC et al. Ocular sequelae in extremely premature infants at 5 years of age. J Paediatr Child Health 1997; 33: 339–42.
Donahue ML, Phelps DL, Watkins RH et al. Retinal vascular endothelial growth factor (VEGF) mRNA expression is altered in relation to neovascularization in oxygen induced retinopathy. Curr Eye Res 1996; 15: 175–84.
Claffey KP, Shih SC, Mullen A et al. Identification of a human VPF/VEGF 3′ untranslated region mediating hypoxia-induced mRNA stability. Mol Biol Cell 1998; 9: 469–81.
Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971; 285: 1182–6.
Tannock IF. The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 1968; 22: 258–73.
Folkman J, Klagsburn M. Angiogenic factors. Science 1987; 235: 442–7.
Lu C, Tanigawa N. Spontaneous apoptosis is inversely related to intratumoral microvessel density in gastric carcinoma. Cancer Res 1997; 57: 221–4.
Jain RK, Safabakhsh N, Sckell A et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor. Proc Natl Acad Sci USA 1998; 95: 10820–5.
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Nör, J.E., Polverini, P.J. Role of endothelial cell survival and death signals in angiogenesis. Angiogenesis 3, 101–116 (1999). https://doi.org/10.1023/A:1009053411094
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DOI: https://doi.org/10.1023/A:1009053411094