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Endothelial cell apoptosis in angiogenesis and vessel regression

Abstract

Blood vessel regression is an essential process for ensuring blood vessel networks function at optimal efficiency and for matching blood supply to the metabolic needs of tissues as they change over time. Angiogenesis is the major mechanism by which new blood vessels are produced, but the vessel growth associated with angiogenesis must be complemented by remodeling and maturation events including the removal of redundant vessel segments and cells to fashion the newly forming vasculature into an efficient, hierarchical network. This review will summarize recent findings on the role that endothelial cell apoptosis plays in vascular remodeling during angiogenesis and in vessel regression more generally.

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Abbreviations

EC:

Endothelial cell

OIR:

Oxygen-induced retinopathy

DISC:

Death-inducing signaling complex

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

References

  1. Neufeld S, Planas-Paz L, Lammert E (2014) Blood and lymphatic vascular tube formation in mouse. Semin Cell Dev Biol 31:115–123

    PubMed  Article  Google Scholar 

  2. Geudens I, Gerhardt H (2011) Coordinating cell behaviour during blood vessel formation. Development 138:4569–4583

    CAS  PubMed  Article  Google Scholar 

  3. Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146:873–887

    CAS  PubMed  Article  Google Scholar 

  4. Siekmann AF, Affolter M, Belting HG (2013) The tip cell concept 10 years after: new players tune in for a common theme. Exp Cell Res 319:1255–1263

    CAS  PubMed  Article  Google Scholar 

  5. Betz C, Lenard A, Belting HG, Affolter M (2016) Cell behaviors and dynamics during angiogenesis. Development 143:2249–2260

    CAS  PubMed  Article  Google Scholar 

  6. Walls JR, Coultas L, Rossant J, Henkelman RM (2008) Three-dimensional analysis of vascular development in the mouse embryo. PLoS One 3:e2853

    PubMed  PubMed Central  Article  Google Scholar 

  7. Modlich U, Kaup FJ, Augustin HG (1996) Cyclic angiogenesis and blood vessel regression in the ovary: blood vessel regression during luteolysis involves endothelial cell detachment and vessel occlusion. Lab Invest 74:771–780

    CAS  PubMed  Google Scholar 

  8. Walker NI, Bennett RE, Kerr JF (1989) Cell death by apoptosis during involution of the lactating breast in mice and rats. Am J Anat 185:19–32

    CAS  PubMed  Article  Google Scholar 

  9. Ito M, Yoshioka M (1999) Regression of the hyaloid vessels and pupillary membrane of the mouse. Anat Embryol 200:403–411

    CAS  PubMed  Article  Google Scholar 

  10. Saint-Geniez M, D’Amore PA (2004) Development and pathology of the hyaloid, choroidal and retinal vasculature. Int J Dev Biol 48:1045–1058

    PubMed  Article  Google Scholar 

  11. Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R, D’Amore PA (1994) Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35:101–111

    CAS  PubMed  Google Scholar 

  12. Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD, McDonald DM (2004) Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 165:35–52

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Baffert F, Thurston G, Rochon-Duck M, Le T, Brekken R, McDonald DM (2004) Age-related changes in vascular endothelial growth factor dependency and angiopoietin-1-induced plasticity of adult blood vessels. Circ Res 94:984–992

    CAS  PubMed  Article  Google Scholar 

  14. Kamba T, Tam BY, Hashizume H, Haskell A, Sennino B, Mancuso MR, Norberg SM, O’Brien SM, Davis RB, Gowen LC, Anderson KD, Thurston G, Joho S, Springer ML, Kuo CJ, McDonald DM (2006) VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol 290:H560–H576

    CAS  PubMed  Article  Google Scholar 

  15. Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell 147:742–758

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Alon T, Hemo I, Itin A, Pe’er J, Stone J, Keshet E (1995) Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1:1024–1028

    CAS  PubMed  Article  Google Scholar 

  17. Yang Y, Zhang Y, Cao Z, Ji H, Yang X, Iwamoto H, Wahlberg E, Lanne T, Sun B, Cao Y (2013) Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues. Proc Natl Acad Sci USA 110:12018–12023

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Baffert F, Le T, Sennino B, Thurston G, Kuo CJ, Hu-Lowe D, McDonald DM (2006) Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol 290:H547–H559

    CAS  PubMed  Article  Google Scholar 

  19. Wang S, Park S, Fei P, Sorenson CM (2011) Bim is responsible for the inherent sensitivity of the developing retinal vasculature to hyperoxia. Dev Biol 349:296–309

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Watson EC, Koenig MN, Grant ZL, Whitehead L, Trounson E, Dewson G, Coultas L (2016) Apoptosis regulates endothelial cell number and capillary vessel diameter but not vessel regression during retinal angiogenesis. Development 143:2973–2982

    CAS  PubMed  Article  Google Scholar 

  21. Koenig MN, Naik E, Rohrbeck L, Herold MJ, Trounson E, Bouillet P, Thomas T, Voss AK, Strasser A, Coultas L (2014) Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3. Cell Death Differ 21:1687–1695

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Hahn P, Lindsten T, Tolentino M, Thompson CB, Bennett J, Dunaief JL (2005) Persistent fetal ocular vasculature in mice deficient in bax and bak. Arch Ophthalmol 123:797–802

    PubMed  Article  Google Scholar 

  23. Naik E, O’Reilly LA, Asselin-Labat ML, Merino D, Lin A, Cook M, Coultas L, Bouillet P, Adams JM, Strasser A (2011) Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells. J Exp Med 208:1351–1358

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163–1177

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, Betsholtz C, Shima DT (2002) Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev 16:2684–2698

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Adams RH, Eichmann A (2010) Axon guidance molecules in vascular patterning. Cold Spring Harb Perspect Biol 2:a001875

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. Jakobsson L, Franco CA, Bentley K, Collins RT, Ponsioen B, Aspalter IM, Rosewell I, Busse M, Thurston G, Medvinsky A, Schulte-Merker S, Gerhardt H (2010) Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat Cell Biol 12:943–953

    CAS  PubMed  Article  Google Scholar 

  28. Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9:685–693

    CAS  PubMed  Article  Google Scholar 

  29. Korn C, Augustin HG (2015) Mechanisms of vessel pruning and regression. Dev Cell 34:5–17

    CAS  PubMed  Article  Google Scholar 

  30. Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10:165–177

    CAS  PubMed  Article  Google Scholar 

  31. Park DY, Lee J, Kim J, Kim K, Hong S, Han S, Kubota Y, Augustin HG, Ding L, Kim JW, Kim H, He Y, Adams RH, Koh GY (2017) Plastic roles of pericytes in the blood-retinal barrier. Nat Commun 8:15296

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Franco CA, Jones ML, Bernabeu MO, Geudens I, Mathivet T, Rosa A, Lopes FM, Lima AP, Ragab A, Collins RT, Phng LK, Coveney PV, Gerhardt H (2015) Dynamic endothelial cell rearrangements drive developmental vessel regression. PLoS Biol 13:e1002125

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. Chen Q, Jiang L, Li C, Hu D, Bu JW, Cai D, Du JL (2012) Haemodynamics-driven developmental pruning of brain vasculature in zebrafish. PLoS Biol 10:e1001374

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Ehling M, Adams S, Benedito R, Adams RH (2013) Notch controls retinal blood vessel maturation and quiescence. Development 140:3051–3061

    CAS  PubMed  Article  Google Scholar 

  35. Stahl A, Connor KM, Sapieha P, Chen J, Dennison RJ, Krah NM, Seaward MR, Willett KL, Aderman CM, Guerin KI, Hua J, Lofqvist C, Hellstrom A, Smith LE (2010) The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci 51:2813–2826

    PubMed  PubMed Central  Article  Google Scholar 

  36. Hughes S, Chang-Ling T (2000) Roles of endothelial cell migration and apoptosis in vascular remodeling during development of the central nervous system. Microcirculation 7:317–333

    CAS  PubMed  Article  Google Scholar 

  37. Korn C, Scholz B, Hu J, Srivastava K, Wojtarowicz J, Arnsperger T, Adams RH, Boutros M, Augustin HG, Augustin I (2014) Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis. Development 141:1757–1766

    CAS  PubMed  Article  Google Scholar 

  38. Gariano RF, Gardner TW (2005) Retinal angiogenesis in development and disease. Nature 438:960–966

    CAS  PubMed  Article  Google Scholar 

  39. Miller JW, Le Couter J, Strauss EC, Ferrara N (2013) Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 120:106–114

    PubMed  Article  Google Scholar 

  40. Scott A, Powner MB, Fruttiger M (2014) Quantification of vascular tortuosity as an early outcome measure in oxygen induced retinopathy (OIR). Exp Eye Res 120:55–60

    CAS  PubMed  Article  Google Scholar 

  41. Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA 92:905–909

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Fukushima Y, Okada M, Kataoka H, Hirashima M, Yoshida Y, Mann F, Gomi F, Nishida K, Nishikawa S, Uemura A (2011) Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice. J Clin Invest 121:1974–1985

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Lobov IB, Cheung E, Wudali R, Cao J, Halasz G, Wei Y, Economides A, Lin HC, Papadopoulos N, Yancopoulos GD, Wiegand SJ (2011) The Dll4/Notch pathway controls postangiogenic blood vessel remodeling and regression by modulating vasoconstriction and blood flow. Blood 117:6728–6737

    CAS  PubMed  Article  Google Scholar 

  44. Mizutani M, Kern TS, Lorenzi M (1996) Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest 97:2883–2890

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Hammes HP, Feng Y, Pfister F, Brownlee M (2011) Diabetic retinopathy: targeting vasoregression. Diabetes 60:9–16

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Green DR, Llambi F (2015) Cell Death Signaling. Cold Spring Harb Perspect Biol 7:a006080

    PubMed  Article  CAS  Google Scholar 

  47. Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G, Korsmeyer SJ, MacGregor GR, Thompson CB (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6:1389–1399

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2:183–192

    CAS  PubMed  Article  Google Scholar 

  50. Llambi F, Moldoveanu T, Tait SW, Bouchier-Hayes L, Temirov J, McCormick LL, Dillon CP, Green DR (2011) A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell 44:517–531

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (2005) Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393–403

    CAS  PubMed  Article  Google Scholar 

  52. Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD (2005) BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17:525–535

    CAS  PubMed  Article  Google Scholar 

  53. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9:351–365

    CAS  PubMed  Article  Google Scholar 

  54. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489

    CAS  PubMed  Article  Google Scholar 

  55. Strasser A, Jost PJ, Nagata S (2009) The many roles of FAS receptor signaling in the immune system. Immunity 30:180–192

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Wilson NS, Dixit V, Ashkenazi A (2009) Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol 10:348–355

    CAS  PubMed  Article  Google Scholar 

  57. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14:5579–5588

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490

    CAS  PubMed  Article  Google Scholar 

  59. Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501

    CAS  PubMed  Article  Google Scholar 

  60. Kaufmann T, Strasser A, Jost PJ (2012) Fas death receptor signalling: roles of Bid and XIAP. Cell Death Differ 19:42–50

    CAS  PubMed  Article  Google Scholar 

  61. de Miguel D, Lemke J, Anel A, Walczak H, Martinez-Lostao L (2016) Onto better TRAILs for cancer treatment. Cell Death Differ 23:733–747

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. Kalliolias GD, Ivashkiv LB (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12:49–62

    CAS  PubMed  Article  Google Scholar 

  63. Pasparakis M, Vandenabeele P (2015) Necroptosis and its role in inflammation. Nature 517:311–320

    CAS  PubMed  Article  Google Scholar 

  64. Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P, Wallach D (1998) Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9:267–276

    CAS  PubMed  Article  Google Scholar 

  65. Alvarez-Diaz S, Dillon CP, Lalaoui N, Tanzer MC, Rodriguez DA, Lin A, Lebois M, Hakem R, Josefsson EC, O’Reilly LA, Silke J, Alexander WS, Green DR, Strasser A (2016) The pseudokinase MLKL and the kinase RIPK3 have distinct roles in autoimmune disease caused by loss of death-receptor-induced apoptosis. Immunity 45:513–526

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T, Mocarski ES (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471:368–372

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR (2011) Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature 471:363–367

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Kang TB, Ben-Moshe T, Varfolomeev EE, Pewzner-Jung Y, Yogev N, Jurewicz A, Waisman A, Brenner O, Haffner R, Gustafsson E, Ramakrishnan P, Lapidot T, Wallach D (2004) Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol 173:2976–2984

    CAS  PubMed  Article  Google Scholar 

  69. Fujio Y, Walsh K (1999) Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem 274:16349–16354

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N (1998) 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 273:30336–30343

    CAS  PubMed  Article  Google Scholar 

  71. Gratton JP, Morales-Ruiz M, Kureishi Y, Fulton D, Walsh K, Sessa WC (2001) Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells. J Biol Chem 276:30359–30365

    CAS  PubMed  Article  Google Scholar 

  72. Carmeliet P, Lampugnani MG, Moons L, Breviario F, Compernolle V, Bono F, Balconi G, Spagnuolo R, Oosthuyse B, Dewerchin M, Zanetti A, Angellilo A, Mattot V, Nuyens D, Lutgens E, Clotman F, de Ruiter MC, Gittenberger-de Groot A, Poelmann R, Lupu F, Herbert JM, Collen D, Dejana E (1999) Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98:147–157

    CAS  PubMed  Article  Google Scholar 

  73. Lobov IB, Brooks PC, Lang RA (2002) Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA 99:11205–11210

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Pierce EA, Foley ED, Smith LE (1996) Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 114:1219–1228

    CAS  PubMed  Article  Google Scholar 

  75. Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S, Ferrara N, Nagy A, Roos KP, Iruela-Arispe ML (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell 130:691–703

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Domigan CK, Warren CM, Antanesian V, Happel K, Ziyad S, Lee S, Krall A, Duan L, Torres-Collado AX, Castellani LW, Elashoff D, Christofk HR, van der Bliek AM, Potente M, Iruela-Arispe ML (2015) Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy. J Cell Sci 128:2236–2248

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Jones N, Master Z, Jones J, Bouchard D, Gunji Y, Sasaki H, Daly R, Alitalo K, Dumont DJ (1999) Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration. J Biol Chem 274:30896–30905

    CAS  PubMed  Article  Google Scholar 

  78. Kim I, Kim HG, So JN, Kim JH, Kwak HJ, Koh GY (2000) Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3′-Kinase/Akt signal transduction pathway. Circ Res 86:24–29

    CAS  PubMed  Article  Google Scholar 

  79. Savant S, La Porta S, Budnik A, Busch K, Hu J, Tisch N, Korn C, Valls AF, Benest AV, Terhardt D, Qu X, Adams RH, Baldwin HS, Ruiz de Almodovar C, Rodewald HR, Augustin HG (2015) The orphan receptor Tie1 controls angiogenesis and vascular remodeling by differentially regulating Tie2 in tip and stalk cells. Cell Rep 12:1761–1773

    CAS  PubMed  Article  Google Scholar 

  80. Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D, Suri C, Campochiaro PA, Wiegand SJ, Yancopoulos GD (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Dev Cell 3:411–423

    CAS  PubMed  Article  Google Scholar 

  81. Rao S, Lobov IB, Vallance JE, Tsujikawa K, Shiojima I, Akunuru S, Walsh K, Benjamin LE, Lang RA (2007) Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch. Development 134:4449–4458

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Hackett SF, Wiegand S, Yancopoulos G, Campochiaro PA (2002) Angiopoietin-2 plays an important role in retinal angiogenesis. J Cell Physiol 192:182–187

    CAS  PubMed  Article  Google Scholar 

  83. Dimmeler S, Zeiher AM (1999) Nitric oxide-an endothelial cell survival factor. Cell Death Differ 6:964–968

    CAS  PubMed  Article  Google Scholar 

  84. Rossig L, Haendeler J, Hermann C, Malchow P, Urbich C, Zeiher AM, Dimmeler S (2000) Nitric oxide down-regulates MKP-3 mRNA levels: involvement in endothelial cell protection from apoptosis. J Biol Chem 275:25502–25507

    CAS  PubMed  Article  Google Scholar 

  85. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM (1999) Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399:601–605

    CAS  PubMed  Article  Google Scholar 

  86. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399:597–601

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Kwon YG, Min JK, Kim KM, Lee DJ, Billiar TR, Kim YM (2001) Sphingosine 1-phosphate protects human umbilical vein endothelial cells from serum-deprived apoptosis by nitric oxide production. J Biol Chem 276:10627–10633

    CAS  PubMed  Article  Google Scholar 

  88. Igarashi J, Bernier SG, Michel T (2001) Sphingosine 1-phosphate and activation of endothelial nitric-oxide synthase. differential regulation of Akt and MAP kinase pathways by EDG and bradykinin receptors in vascular endothelial cells. J Biol Chem 276:12420–12426

    CAS  PubMed  Article  Google Scholar 

  89. Rutherford C, Childs S, Ohotski J, McGlynn L, Riddick M, MacFarlane S, Tasker D, Pyne S, Pyne NJ, Edwards J, Palmer TM (2013) Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1. Cell Death Dis 4:e927

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Nofer JR, van der Giet M, Tolle M, Wolinska I, von Wnuck Lipinski K, Baba HA, Tietge UJ, Godecke A, Ishii I, Kleuser B, Schafers M, Fobker M, Zidek W, Assmann G, Chun J, Levkau B (2004) HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest 113:569–581

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Gaengel K, Niaudet C, Hagikura K, Lavina B, Muhl L, Hofmann JJ, Ebarasi L, Nystrom S, Rymo S, Chen LL, Pang MF, Jin Y, Raschperger E, Roswall P, Schulte D, Benedito R, Larsson J, Hellstrom M, Fuxe J, Uhlen P, Adams R, Jakobsson L, Majumdar A, Vestweber D, Uv A, Betsholtz C (2012) The sphingosine-1-phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE-cadherin and VEGFR2. Dev Cell 23:587–599

    CAS  PubMed  Article  Google Scholar 

  92. Isermann B, Vinnikov IA, Madhusudhan T, Herzog S, Kashif M, Blautzik J, Corat MA, Zeier M, Blessing E, Oh J, Gerlitz B, Berg DT, Grinnell BW, Chavakis T, Esmon CT, Weiler H, Bierhaus A, Nawroth PP (2007) Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med 13:1349–1358

    CAS  PubMed  Article  Google Scholar 

  93. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266:1865–1869

    CAS  PubMed  Article  Google Scholar 

  94. Montaner S, Sodhi A, Pece S, Mesri EA, Gutkind JS (2001) The Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor promotes endothelial cell survival through the activation of Akt/protein kinase B. Cancer Res 61:2641–2648

    CAS  PubMed  Google Scholar 

  95. Zhande R, Karsan A (2007) Erythropoietin promotes survival of primary human endothelial cells through PI3K-dependent, NF-kappaB-independent upregulation of Bcl-xL. Am J Physiol Heart Circ Physiol 292:H2467–H2474

    CAS  PubMed  Article  Google Scholar 

  96. Karsan A, Yee E, Poirier GG, Zhou P, Craig R, Harlan JM (1997) Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. Am J Pathol 151:1775–1784

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Araki S, Simada Y, Kaji K, Hayashi H (1990) Role of protein kinase C in the inhibition by fibroblast growth factor of apoptosis in serum-depleted endothelial cells. Biochem Biophys Res Commun 172:1081–1085

    CAS  PubMed  Article  Google Scholar 

  98. Chavakis E, Dimmeler S (2002) Regulation of endothelial cell survival and apoptosis during angiogenesis. Arterioscler Thromb Vasc Biol 22:887–893

    CAS  PubMed  Article  Google Scholar 

  99. Baeyens N, Bandyopadhyay C, Coon BG, Yun S, Schwartz MA (2016) Endothelial fluid shear stress sensing in vascular health and disease. J Clin Invest 126:821–828

    PubMed  PubMed Central  Article  Google Scholar 

  100. Zhou J, Li YS, Chien S (2014) Shear stress-initiated signaling and its regulation of endothelial function. Arterioscler Thromb Vasc Biol 34:2191–2198

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Dimmeler S, Assmus B, Hermann C, Haendeler J, Zeiher AM (1998) Fluid shear stress stimulates phosphorylation of Akt in human endothelial cells: involvement in suppression of apoptosis. Circ Res 83:334–341

    CAS  PubMed  Article  Google Scholar 

  102. Shay-Salit A, Shushy M, Wolfovitz E, Yahav H, Breviario F, Dejana E, Resnick N (2002) VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc Natl Acad Sci USA 99:9462–9467

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Jin ZG, Ueba H, Tanimoto T, Lungu AO, Frame MD, Berk BC (2003) Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase. Circ Res 93:354–363

    CAS  PubMed  Article  Google Scholar 

  104. Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, Kratz JR, Lin Z, Jain MK, Gimbrone MA Jr, Garcia-Cardena G (2006) Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Invest 116:49–58

    CAS  PubMed  Article  Google Scholar 

  105. Abe J, Berk BC (2014) Novel mechanisms of endothelial mechanotransduction. Arterioscler Thromb Vasc Biol 34:2378–2386

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Lee HJ, Koh GY (2003) Shear stress activates Tie2 receptor tyrosine kinase in human endothelial cells. Biochem Biophys Res Commun 304:399–404

    CAS  PubMed  Article  Google Scholar 

  107. Le NT, Heo KS, Takei Y, Lee H, Woo CH, Chang E, McClain C, Hurley C, Wang X, Li F, Xu H, Morrell C, Sullivan MA, Cohen MS, Serafimova IM, Taunton J, Fujiwara K, Abe J (2013) A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis. Circulation 127:486–499

    CAS  PubMed  Article  Google Scholar 

  108. Darland DC, Massingham LJ, Smith SR, Piek E, Saint-Geniez M, D’Amore PA (2003) Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev Biol 264:275–288

    CAS  PubMed  Article  Google Scholar 

  109. Benjamin LE, Hemo I, Keshet E (1998) 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 125:1591–1598

    CAS  PubMed  Google Scholar 

  110. Fruttiger M (2002) Development of the mouse retinal vasculature: angiogenesis versus vasculogenesis. Invest Ophthalmol Vis Sci 43:522–527

    PubMed  Google Scholar 

  111. Wang S, Zaitoun IS, Johnson RP, Jamali N, Gurel Z, Wintheiser CM, Strasser A, Lindner V, Sheibani N, Sorenson CM (2017) Bim expression in endothelial cells and pericytes is essential for regression of the fetal ocular vasculature. PLoS One 12:e0178198

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. Wilhelm K, Happel K, Eelen G, Schoors S, Oellerich MF, Lim R, Zimmermann B, Aspalter IM, Franco CA, Boettger T, Braun T, Fruttiger M, Rajewsky K, Keller C, Bruning JC, Gerhardt H, Carmeliet P, Potente M (2016) FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature 529:216–220

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E (1999) Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 103:159–165

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Nisancioglu MH, Betsholtz C, Genove G (2010) The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor-A blockade. Cancer Res 70:5109–5115

    CAS  PubMed  Article  Google Scholar 

  115. Simonavicius N, Ashenden M, van Weverwijk A, Lax S, Huso DL, Buckley CD, Huijbers IJ, Yarwood H, Isacke CM (2012) Pericytes promote selective vessel regression to regulate vascular patterning. Blood 120:1516–1527

    CAS  PubMed  Article  Google Scholar 

  116. Czymai T, Viemann D, Sticht C, Molema G, Goebeler M, Schmidt M (2010) FOXO3 modulates endothelial gene expression and function by classical and alternative mechanisms. J Biol Chem 285:10163–10178

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Coultas L, Bouillet P, Stanley EG, Brodnicki TC, Adams JM, Strasser A (2004) Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death. Mol Cell Biol 24:1570–1581

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Zhang F, Li Y, Tang Z, Kumar A, Lee C, Zhang L, Zhu C, Klotzsche-von Ameln A, Wang B, Gao Z, Zhang S, Langer HF, Hou X, Jensen L, Ma W, Wong W, Chavakis T, Liu Y, Cao Y, Li X (2012) Proliferative and survival effects of PUMA promote angiogenesis. Cell Rep 2:1272–1285

    CAS  PubMed  Article  Google Scholar 

  119. Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63

    CAS  PubMed  Article  Google Scholar 

  120. Watson EC, Whitehead L, Adams RH, Dewson G, Coultas L (2016) Endothelial cell survival during angiogenesis requires the pro-survival protein MCL1. Cell Death Differ 23:1371–1379

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Thurston G, Noguera-Troise I, Yancopoulos GD (2007) The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer 7:327–331

    CAS  PubMed  Article  Google Scholar 

  122. Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams RH (2009) The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137:1124–1135

    CAS  PubMed  Article  Google Scholar 

  123. Gerber HP, Dixit V, Ferrara N (1998) Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 273:13313–13316

    CAS  PubMed  Article  Google Scholar 

  124. Nor JE, Christensen J, Mooney DJ, Polverini PJ (1999) Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol 154:375–384

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Zaitoun IS, Johnson RP, Jamali N, Almomani R, Wang S, Sheibani N, Sorenson CM (2015) Endothelium expression of Bcl-2 is essential for normal and pathological ocular vascularization. PLoS One 10:e0139994

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. Franco M, Roswall P, Cortez E, Hanahan D, Pietras K (2011) Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression. Blood 118:2906–2917

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Print CG, Loveland KL, Gibson L, Meehan T, Stylianou A, Wreford N, de Kretser D, Metcalf D, Kontgen F, Adams JM, Cory S (1998) Apoptosis regulator bcl-w is essential for spermatogenesis but appears otherwise redundant. Proc Natl Acad Sci USA 95:12424–12431

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Lindqvist LM, Heinlein M, Huang DC, Vaux DL (2014) Prosurvival Bcl-2 family members affect autophagy only indirectly, by inhibiting Bax and Bak. Proc Natl Acad Sci USA 111:8512–8517

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Duriez PJ, Wong F, Dorovini-Zis K, Shahidi R, Karsan A (2000) A1 functions at the mitochondria to delay endothelial apoptosis in response to tumor necrosis factor. J Biol Chem 275:18099–18107

    CAS  PubMed  Article  Google Scholar 

  130. Karsan A, Yee E, Kaushansky K, Harlan JM (1996) Cloning of human Bcl-2 homologue: inflammatory cytokines induce human A1 in cultured endothelial cells. Blood 87:3089–3096

    CAS  PubMed  Google Scholar 

  131. Schenk RL, Tuzlak S, Carrington EM, Zhan Y, Heinzel S, Teh CE, Gray DH, Tai L, Lew AM, Villunger A, Strasser A, Herold MJ (2017) Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment. Cell Death Differ 24:534–545

    CAS  PubMed  Article  Google Scholar 

  132. Wei G, Srinivasan R, Cantemir-Stone CZ, Sharma SM, Santhanam R, Weinstein M, Muthusamy N, Man AK, Oshima RG, Leone G, Ostrowski MC (2009) Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis. Blood 114:1123–1130

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. Lee YH, Mungunsukh O, Tutino RL, Marquez AP, Day RM (2010) Angiotensin-II-induced apoptosis requires regulation of nucleolin and Bcl-xL by SHP-2 in primary lung endothelial cells. J Cell Sci 123:1634–1643

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Motoyama N, Wang F, Roth KA, Sawa H, Nakayama K, Negishi I, Senju S, Zhang Q, Fujii S et al (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267:1506–1510

    CAS  PubMed  Article  Google Scholar 

  135. Vikstrom IB, Slomp A, Carrington EM, Moesbergen LM, Chang C, Kelly GL, Glaser SP, Jansen JH, Leusen JH, Strasser A, Huang DC, Lew AM, Peperzak V, Tarlinton DM (2016) MCL-1 is required throughout B-cell development and its loss sensitizes specific B-cell subsets to inhibition of BCL-2 or BCL-XL. Cell Death Dis 7:e2345

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. Dzhagalov I, Dunkle A, He YW (2008) The anti-apoptotic Bcl-2 family member Mcl-1 promotes T lymphocyte survival at multiple stages. J Immunol 181:521–528

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Khaw SL, Merino D, Anderson MA, Glaser SP, Bouillet P, Roberts AW, Huang DC (2014) Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199. Leukemia 28:1207–1215

    CAS  PubMed  Article  Google Scholar 

  138. Ishida S, Yamashiro K, Usui T, Kaji Y, Ogura Y, Hida T, Honda Y, Oguchi Y, Adamis AP (2003) Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease. Nat Med 9:781–788

    CAS  PubMed  Article  Google Scholar 

  139. Barreiro R, Schadlu R, Herndon J, Kaplan HJ, Ferguson TA (2003) The role of Fas-FasL in the development and treatment of ischemic retinopathy. Invest Ophthalmol Vis Sci 44:1282–1286

    PubMed  Article  Google Scholar 

  140. Davies MH, Eubanks JP, Powers MR (2003) Increased retinal neovascularization in Fas ligand-deficient mice. Invest Ophthalmol Vis Sci 44:3202–3210

    PubMed  Article  Google Scholar 

  141. Kaplan HJ, Leibole MA, Tezel T, Ferguson TA (1999) Fas ligand (CD95 ligand) controls angiogenesis beneath the retina. Nat Med 5:292–297

    CAS  PubMed  Article  Google Scholar 

  142. Cantarella G, Di Benedetto G, Ribatti D, Saccani-Jotti G, Bernardini R (2014) Involvement of caspase 8 and c-FLIPL in the proangiogenic effects of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). FEBS J 281:1505–1513

    CAS  PubMed  Article  Google Scholar 

  143. Hubert KE, Davies MH, Stempel AJ, Griffith TS, Powers MR (2009) TRAIL-deficient mice exhibit delayed regression of retinal neovascularization. Am J Pathol 175:2697–2708

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. Wilson NS, Yang A, Yang B, Couto S, Stern H, Gogineni A, Pitti R, Marsters S, Weimer RM, Singh M, Ashkenazi A (2012) Proapoptotic activation of death receptor 5 on tumor endothelial cells disrupts the vasculature and reduces tumor growth. Cancer Cell 22:80–90

    CAS  PubMed  Article  Google Scholar 

  145. Meeson A, Palmer M, Calfon M, Lang R (1996) A relationship between apoptosis and flow during programmed capillary regression is revealed by vital analysis. Development 122:3929–3938

    CAS  PubMed  Google Scholar 

  146. Poche RA, Hsu CW, McElwee ML, Burns AR, Dickinson ME (2015) Macrophages engulf endothelial cell membrane particles preceding pupillary membrane capillary regression. Dev Biol 403:30–42

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M, Ondr JK, Kurup S, Glass DA, Patel MS, Shu W, Morrisey EE, McMahon AP, Karsenty G, Lang RA (2005) WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437:417–421

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. Rao S, Chun C, Fan J, Kofron JM, Yang MB, Hegde RS, Ferrara N, Copenhagen DR, Lang RA (2013) A direct and melanopsin-dependent fetal light response regulates mouse eye development. Nature 494:243–246

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. Okabe K, Kobayashi S, Yamada T, Kurihara T, Tai-Nagara I, Miyamoto T, Mukouyama YS, Sato TN, Suda T, Ema M, Kubota Y (2014) Neurons limit angiogenesis by titrating VEGF in retina. Cell 159:584–596

    CAS  PubMed  Article  Google Scholar 

  150. Ashton N (1966) Oxygen and the growth and development of retinal vessels. In vivo and in vitro studies. The XX Francis I. Proctor Lecture. Am J Ophthalmol 62:412–435

    CAS  PubMed  Article  Google Scholar 

  151. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Claxton S, Fruttiger M (2003) Role of arteries in oxygen induced vaso-obliteration. Exp Eye Res 77:305–311

    CAS  PubMed  Article  Google Scholar 

  153. Scholz B, Korn C, Wojtarowicz J, Mogler C, Augustin I, Boutros M, Niehrs C, Augustin HG (2016) Endothelial RSPO3 controls vascular stability and pruning through non-canonical WNT/Ca(2+)/NFAT signaling. Dev Cell 36:79–93

    CAS  PubMed  Article  Google Scholar 

  154. Cheng C, Haasdijk R, Tempel D, van de Kamp EH, Herpers R, Bos F, Den Dekker WK, Blonden LA, de Jong R, Burgisser PE, Chrifi I, Biessen EA, Dimmeler S, Schulte-Merker S, Duckers HJ (2012) Endothelial cell-specific FGD5 involvement in vascular pruning defines neovessel fate in mice. Circulation 125:3142–3158

    PubMed  Article  Google Scholar 

  155. Franco CA, Jones ML, Bernabeu MO, Vion AC, Barbacena P, Fan J, Mathivet T, Fonseca CG, Ragab A, Yamaguchi TP, Coveney PV, Lang RA, Gerhardt H (2016) Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling. Elife 5:e07727

    PubMed  PubMed Central  Google Scholar 

  156. Grutzmacher C, Park S, Elmergreen TL, Tang Y, Scheef EA, Sheibani N, Sorenson CM (2010) Opposing effects of bim and bcl-2 on lung endothelial cell migration. Am J Physiol Lung Cell Mol Physiol 299:L607–L620

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Sheibani N, Morrison ME, Gurel Z, Park S, Sorenson CM (2012) BIM deficiency differentially impacts the function of kidney endothelial and epithelial cells through modulation of their local microenvironment. Am J Physiol Renal Physiol 302:F809–F819

    PubMed  Article  Google Scholar 

  158. Kochhan E, Lenard A, Ellertsdottir E, Herwig L, Affolter M, Belting HG, Siekmann AF (2013) Blood flow changes coincide with cellular rearrangements during blood vessel pruning in zebrafish embryos. PLoS One 8:e75060

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. Lenard A, Daetwyler S, Betz C, Ellertsdottir E, Belting HG, Huisken J, Affolter M (2015) Endothelial cell self-fusion during vascular pruning. PLoS Biol 13:e1002126

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  160. Bernabeu MO, Jones ML, Nielsen JH, Kruger T, Nash RW, Groen D, Schmieschek S, Hetherington J, Gerhardt H, Franco CA, Coveney PV (2014) Computer simulations reveal complex distribution of haemodynamic forces in a mouse retina model of angiogenesis. J R Soc Interface 11:20140543

    PubMed  PubMed Central  Article  Google Scholar 

  161. Bartling B, Tostlebe H, Darmer D, Holtz J, Silber RE, Morawietz H (2000) Shear stress-dependent expression of apoptosis-regulating genes in endothelial cells. Biochem Biophys Res Commun 278:740–746

    CAS  PubMed  Article  Google Scholar 

  162. Hammes HP, Lin J, Wagner P, Feng Y, Vom Hagen F, Krzizok T, Renner O, Breier G, Brownlee M, Deutsch U (2004) Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes 53:1104–1110

    CAS  PubMed  Article  Google Scholar 

  163. Yao D, Taguchi T, Matsumura T, Pestell R, Edelstein D, Giardino I, Suske G, Ahmed N, Thornalley PJ, Sarthy VP, Hammes HP, Brownlee M (2007) Methylglyoxal modification of mSin3A links glycolysis to angiopoietin-2 transcription. Cell 128:625

    CAS  PubMed  Article  Google Scholar 

  164. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487

    CAS  PubMed  Article  Google Scholar 

  165. van den Oever IA, Raterman HG, Nurmohamed MT, Simsek S (2010) Endothelial dysfunction, inflammation, and apoptosis in diabetes mellitus. Mediat Inflamm 2010:792393

    Google Scholar 

  166. Maric-Bilkan C, Flynn ER, Chade AR (2012) Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat. Am J Physiol Renal Physiol 302:F308–F315

    CAS  PubMed  Article  Google Scholar 

  167. Ido Y, Carling D, Ruderman N (2002) Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes 51:159–167

    CAS  PubMed  Article  Google Scholar 

  168. Quagliaro L, Piconi L, Assaloni R, Martinelli L, Motz E, Ceriello A (2003) Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)H-oxidase activation. Diabetes 52:2795–2804

    CAS  PubMed  Article  Google Scholar 

  169. Yang Z, Mo X, Gong Q, Pan Q, Yang X, Cai W, Li C, Ma JX, He Y, Gao G (2008) Critical effect of VEGF in the process of endothelial cell apoptosis induced by high glucose. Apoptosis 13:1331–1343

    CAS  PubMed  Article  Google Scholar 

  170. Lindenmeyer MT, Kretzler M, Boucherot A, Berra S, Yasuda Y, Henger A, Eichinger F, Gaiser S, Schmid H, Rastaldi MP, Schrier RW, Schlondorff D, Cohen CD (2007) Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy. J Am Soc Nephrol 18:1765–1776

    CAS  PubMed  Article  Google Scholar 

  171. Sivaskandarajah GA, Jeansson M, Maezawa Y, Eremina V, Baelde HJ, Quaggin SE (2012) Vegfa protects the glomerular microvasculature in diabetes. Diabetes 61:2958–2966

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

The work of the authors is supported by the National Health and Medical Research Council, Australia (Project Grant: 1125536), Australian Government Research Training Program Scholarships (to ECW and ZLG), and the L.E.W Carty Charitable Fund. The work is made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.

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Watson, E.C., Grant, Z.L. & Coultas, L. Endothelial cell apoptosis in angiogenesis and vessel regression. Cell. Mol. Life Sci. 74, 4387–4403 (2017). https://doi.org/10.1007/s00018-017-2577-y

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  • DOI: https://doi.org/10.1007/s00018-017-2577-y

Keywords

  • Vessel pruning
  • BCL2
  • Death receptors
  • Diabetes
  • Diabetic retinopathy