Ординатура / Офтальмология / Английские материалы / Retinal and Choroidal Angiogenesis_Penn_2008

mobilizing and chemotactic abilities. These factors are expressed after tissue is injured and are involved in both normal repair and patho-physiological healing processes. SDF-1 and VEGF are critically important to endothelial repair and neoangiogenesis. The future therapeutic application of EPCs must consider that these cells themselves are capable of secreting growth factors to modulate local vascular repair. EPCs may also need to be directed to injured tissue for optimal localization, and the timing of the administration of these cells will be critical. EPC contributions to pathological repair must also be carefully considered when directing treatment strategies.

REFERENCES

1.P. Libby, M. Aikawa, S. Kinlay, A. Selwyn and P. Ganz, Lipid lowering improves endothelial functions, Int. J. Cardiol. 74 Suppl 1, S3-S10, (2000).

2.S. Verma, A. Maitland, R. D. Weisel, P. W. Fedak, S. H. Li, D. A. Mickle, R. K. Li,

L.Ko and V. Rao, Increased endothelin-1 production in diabetic patients after cardioplegic arrest and reperfusion impairs coronary vascular reactivity: reversal by means of endothelin antagonism, J. Thorac. Cardiovasc. Surg. 123(6), 1114-1119, (2002).

3.F. George, P. Poncelet, J. C. Laurent, O. Massot, D. Arnoux, N. Lequeux, P. Ambrosi,

C.Chicheportiche and J. Sampol, Cytofluorometric detection of human endothelial cells in whole blood using S-Endo 1 monoclonal antibody, J. Immunol. Methods, 139(1), 65-75, (1991).

4.M. Mutin, I. Canavy, A. Blann, M. Bory, J. Sampol and F. Dignat-George, Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells, Blood, 93(9), 2951-2958, (1999).

5.A. Woywodt, F. H. Bahlmann, K. De Groot, H. Haller and M. Haubitz, Circulating endothelial cells: life, death, detachment and repair of the endothelial cell layer, Nephrol. Dial. Transplant., 17(10), 1728-1730, (2002).

6.A. Luttun, G. Carmeliet and P. Carmeliet, Vascular progenitors: from biology to treatment, Trends Cardiovasc. Med. 12(2), 88-96, (2002).

7.T. Asahara, T. Murohara, A. Sullivan, M. Silver, R. van der Zee, T. Li, B. Witzenbichler,

G.Schatteman and J. M. Isner, Isolation of putative progenitor endothelial cells for angiogenesis, Science, 275(5302), 964-967, (1997).

8.D. H. Walter and S. Dimmeler, Endothelial progenitor cells: regulation and contribution to adult neovascularization, Herz. 27(7), 579-588, (2002).

9.M. Peichev, A. J. Naiyer, D. Pereira, Z. Zhu, W. J. Lane, M. Williams, M. C. Oz,

D.J. Hicklin, L. Witte, M. A. Moore and S. Rafii, Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors, Blood, 95(3), 952-958, (2000).

10.A. H. Yin, S. Miraglia, E. D. Zanjani, G. Almeida-Porada, M. Ogawa, A. G. Leary,

J.Olweus, J. Kearney and D. W. Buck, AC133, a novel marker for human hematopoietic stem and progenitor cells, Blood, 90(12), 5002-5012, (1997).

11.U. M. Gehling, S. Ergun, U. Schumacher, C. Wagener, K. Pantel, M. Otte, G. Schuch,

P.Schafhausen, T. Mende, N. Kilic, K. Kluge, B. Schafer, D. K. Hossfeld and W. Fiedler, In vitro differentiation of endothelial cells from AC133-positive progenitor cells, Blood, 95(10), 3106-3112, (2000).

12.N. Quirici, D. Soligo, L. Caneva, F. Servida, P. Bossolasco and G. L. Deliliers, Differentiation and expansion of endothelial cells from human bone marrow CD133(+) cells, Br. J. Haematol. 115(1), 186-194, (2001).

13.J. R. Crosby, W. E. Kaminski, G. Schatteman, P. J. Martin, E. W. Raines, R. A. Seifert and D. F. Bowen-Pope, Endothelial cells of hematopoietic origin make a significant contribution to adult blood vessel formation, Circ. Res. 87(9), 728-730, (2000).

14.T. Asahara, H. Masuda, T. Takahashi, C. Kalka, C. Pastore, M. Silver, M. Kearne,

M.Magner and J. M. Isner, Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization, Circ. Res. 85(3), 221-228, (1999).

15.D. E. Wright, A. J. Wagers, A. P. Gulati, F. L. Johnson and I. L. Weissman, Physiological migration of hematopoietic stem and progenitor cells, Science, 294(5548), 1933-1936, (2001).

16.Q. Shi, S. Rafii, M. H. Wu, E. S. Wijelath, C. Yu, A. Ishida, Y. Fujita, S. Kothari,

R.Mohle, L. R. Sauvage, M. A. Moore, R. F. Storb and W. P. Hammond, Evidence for circulating bone marrow-derived endothelial cells, Blood, 92(2), 362-367, (1998).

17.N. Werner, J. Priller, U. Laufs, M. Endres, M. Bohm, U. Dirnagl and G. Nickenig, Bone marrow-derived progenitor cells modulate vascular reendothelialization and neointimal formation: effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition,

Arterioscler. Thromb. Vasc. Biol. 22(10), 1567-1572, (2002).

18.J. Folkman, Angiogenesis in cancer, vascular, rheumatoid and other disease, Nat. Med. 1(1), 27-31, (1995).

19.P. Carmeliet, Developmental biology. One cell, two fates, Nature, 408(6808), 43-45, (2000).

20.S. Rafii, B. Heissig and K. Hattori, Efficient mobilization and recruitment of marrowderived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors, Gene Ther. 9(10), 631-641, (2002).

21.T. Takahashi, C. Kalka, H. Masuda, D. Chen, M. Silver, M. Kearney, M. Magner,

J.M. Isner and T. Asahara, Ischemiaand cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization, Nat. Med. 5(4), 434-438, (1999).

22.S. Shintani, T. Murohara, H. Ikeda, T. Ueno, T. Honma, A. Katoh, K. Sasaki, T. Shimada,

Y.Oike and T. Imaizumi, Mobilization of endothelial progenitor cells in patients with acute myocardial infarction, Circulation, 103(23), 2776-2779, (2001).

23.K. Hattori, S. Dias, B. Heissig, N. R. Hackett, D. Lyden, M. Tateno, D. J. Hicklin,

Z.Zhu, L. Witte, R. G. Crystal, M. A. Moore and S. Rafii, Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells, J. Exp. Med. 193(9), 1005-1014 (2001).

24.C. Kalka, H. Masuda, T. Takahashi, R. Gordon, O. Tepper, E. Gravereaux, A. Pieczek,

H.Iwaguro, S. I. Hayashi, J. M. Isner and T. Asahara, Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects, Circ. Res. 86(12), 1198-1202 (2000).

25.I. Flamme, M. von Reutern, H. C. Drexler, S. Syed-Ali and W. Risau, Overexpression of vascular endothelial growth factor in the avian embryo induces hypervascularization and increased vascular permeability without alterations of embryonic pattern formation, Dev.

Biol. 171(2), 399-414 (1995).

26. P. Carmeliet, V. Ferreira, G. Breier, S. Pollefeyt, L. Kieckens, M. Gertsenstein, M. Fahrig, A. Vandenhoeck, K. Harpal, C. Eberhardt, C. Declercq, J. Pawling, L. Moons, D. Collen, W. Risau and A. Nagy, Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele, Nature, 380(6573), 435-439 (1996).

27.S. Rafii, D. Lyden, R. Benezra, K. Hattori and B. Heissig, Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat. Rev. Cancer, 2(11), 826-835 (2002).

28.J. Yamaguchi, K. F. Kusano, O. Masuo, A. Kawamoto, M. Silver, S. Murasawa,

M.Bosch-Marce, H. Masuda, D. W. Losordo, J. M. Isner and T. Asahara, Stromal cellderived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization, Circulation, 107(9), 1322-1328 (2003).

29.F. Bautz, S. Rafii, L. Kanz and R. Mohle, Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hematopoietic progenitor cells. Possible role in the hematopoietic microenvironment, Exp. Hematol. 28(6), 700-706 (2000).

30.C. Seiler, T. Pohl, K. Wustmann, D. Hutter, P. A. Nicolet, S. Windecker, F. R. Eberli and

B.Meier, Promotion of collateral growth by granulocyte-macrophage colony-stimulating factor in patients with coronary artery disease: a randomized, double-blind, placebocontrolled study, Circulation, 104(17), 2012-2017 (2001).

31.A. A. Kocher, M. D. Schuster, M. J. Szabolcs, S. Takuma, D. Burkhoff, J. Wang,

S.Homma, N. M. Edwards and S. Itescu, Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function, Nat. Med. 7(4), 430-436 (2001).

32.B. Heissig, K. Hattori, S. Dias, M. Friedrich, B. Ferris, N. R. Hackett, R. G. Crystal,

P.Besmer, D. Lyden, M. A. Moore, Z. Werb and S. Rafii, Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kitligand, Cell, 109(5), 625-637 (2002).

33.K. Hattori, B. Heissig, Y. Wu, S. Dias, R. Tejada, B. Ferris, D. J. Hicklin, Z. Zhu,

P.Bohlen, L. Witte, J. Hendrikx, N. R. Hackett, R. G. Crystal, M. A. Moore, Z. Werb,

D.Lyden and S. Rafii, Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment, Nat. Med. 8(8), 841-849 (2002).

34.M. B. Grant, W. S. May, S. Caballero, G. A. Brown, S. M. Guthrie, R. N. Mames,

B.J. Byrne, T. Vaught, P. E. Spoerri, A. B. Peck and E. W. Scott, Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization, Nat. Med. 8(6), 607-612 (2002).

35.P. M. Murphy, Viral antichemokines: from pathogenesis to drug discovery, J. Clin. Invest. 105(11), 1515-1517 (2000).

36.K. Tashiro, H. Tada, R. Heilker, M. Shirozu, T. Nakano and T. Honjo, Signal sequence trap: a cloning strategy for secreted proteins and type I membrane proteins, Science, 261(5121), 600-603 (1993).

37.A. Aiuti, I. J. Webb, C. Bleul, T. Springer and J. C. Gutierrez-Ramos, The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood, J. Exp. Med. 185(1), 111-120 (1997).

38.C. C. Bleul, M. Farzan, H. Choe, C. Parolin, I. Clark-Lewis, J. Sodroski and T. A. Springer, The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry, Nature, 382(6594), 829-833 (1996).

39.E. Oberlin, A. Amara, F. Bachelerie, C. Bessia, J. L. Virelizier, F. Arenzana-Seisdedos,

O.Schwartz, J. M. Heard, I. Clark-Lewis, D. F. Legler, M. Loetscher, M. Baggiolini and

B.Moser, The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1, Nature, 382(6594), 833-835 (1996).

40.Y. Feng, C. C. Broder, P. E. Kennedy and E. A. Berger, HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor, Science, 272(5263), 872-877 (1996).

41.T. Nagasawa, S. Hirota, K. Tachibana, N. Takakura, S. Nishikawa, Y. Kitamura,

N.Yoshida, H. Kikutani and T. Kishimoto, Defects of B-cell lymphopoiesis and bonemarrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1, Nature, 382(6592), 635-638 (1996).

42.K. Tachibana, S. Hirota, H. Iizasa, H. Yoshida, K. Kawabata, Y. Kataoka, Y. Kitamura,

K.Matsushima, N. Yoshida, S. Nishikawa, T. Kishimoto and T. Nagasawa, The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract, Nature, 393(6685), 591-594 (1998).

43.C. Murdoch, P. N. Monk and A. Finn, Cxc chemokine receptor expression on human endothelial cells, Cytokine, 11(9), 704-712 (1999).

44.R. Salcedo, K. Wasserman, H. A. Young, M. C. Grimm, O. M. Howard, M. R. Anver,

H.K. Kleinman, W. J. Murphy and J. J. Oppenheim, Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha, Am. J. Pathol. 154(4), 1125-1135 (1999).

45.J. Kijowski, M. Baj-Krzyworzeka, M. Majka, R. Reca, L. A. Marquez, M. ChristofidouSolomidou, A. Janowska-Wieczorek and M. Z. Ratajczak, The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells, Stem Cells, 19(5), 453-466 (2001).

46.D. J. Ceradini and G. C. Gurtner, Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue, Trends Cardiovasc Med, 15(2), 57-63 (2005).

47.J. Ma, J. Ge, S. Zhang, A. Sun, J. Shen, L. Chen, K. Wang and Y. Zou, Time course of myocardial stromal cell-derived factor 1 expression and beneficial effects of intravenously administered bone marrow stem cells in rats with experimental myocardial infarction, Basic Res. Cardiol. 100(3), 217-223 (2005).

48.O. Salvucci, M. Basik, L. Yao, R. Bianchi and G. Tosato, Evidence for the involvement of SDF-1 and CXCR4 in the disruption of endothelial cell-branching morphogenesis and angiogenesis by TNF-alpha and IFN-gamma, J. Leukoc. Biol. 76(1), 217-226 (2004).

49.E. De Falco, D. Porcelli, A. R. Torella, S. Straino, M. G. Iachininoto, A. Orlandi,

S.Truffa, P. Biglioli, M. Napolitano, M. C. Capogrossi and M. Pesce, SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells, Blood, 104(12), 3472-3482 (2004).

50.J. Wang, J. Wang, Y. Sun, W. Song, J. E. Nor, C. Y. Wang and R. S. Taichman, Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis, Cell Signal. (2005).

51.B. Guleng, K. Tateishi, M. Ohta, F. Kanai, A. Jazag, H. Ijichi, Y. Tanaka, M. Washida,

K.Morikane, Y. Fukushima, T. Yamori, T. Tsuruo, T. Kawabe, M. Miyagishi, K. Taira,

M.Sata and M. Omata, Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner, Cancer Res. 65(13), 5864-5871 (2005).

52.H. L. Brooks, Jr., S. Caballero, Jr., C. K. Newell, R. L. Steinmetz, D. Watson, M. S. Segal,

J.K. Harrison, E. W. Scott and M. B. Grant, Vitreous levels of vascular endothelial growth factor and stromal-derived factor 1 in patients with diabetic retinopathy and cystoid macular edema before and after intraocular injection of triamcinolone, Arch. Ophthalmol. 122(12), 1801-1807 (2004).

53.J. M. Butler, S. M. Guthrie, M. Koc, A. Afzal, S. Caballero, H. L. Brooks, R. N. Mames,

M.S. Segal, M. B. Grant and E. W. Scott, SDF-1 is both necessary and sufficient to promote proliferative retinopathy, J. Clin. Invest. 115(1), 86-93 (2005).

54.N. Sengupta, S. Caballero, R. N. Mames, A. M. Timmers, D. Saban and M. B. Grant, Preventing stem cell incorporation into choroidal neovascularization by targeting homing and attachment factors, Invest. Ophthalmol. Vis. Sci. 46(1), 343-348 (2005).

55.T. L. Huber, V. Kouskoff, H. J. Fehling, J. Palis and G. Keller, Haemangioblast commitment is initiated in the primitive streak of the mouse embryo, Nature, 432(7017), 625-630 (2004).

56.S. M. Guthrie, L. M. Curtis, R. N. Mames, G. G. Simon, M. B. Grant and E. W. Scott, The nitric oxide pathway modulates hemangioblast activity of adult hematopoietic stem cells, Blood, 105(5), 1916-1922 (2005).

57.R. Ross, J. Glomset and L. Harker, Response to injury and atherogenesis, Am. J. Pathol. 86(3), 675-684 (1977).

58.Y. Mitamura, S. Takeuchi, A. Matsuda, Y. Tagawa, Y. Mizue and J. Nishihira, Monocyte chemotactic protein-1 in the vitreous of patients with proliferative diabetic retinopathy, Ophthalmologica, 215(6), 415-418 (2001).

59.D. J. Maron, S. Fazio and M. F. Linton, Current perspectives on statins, Circulation, 101(2), 207-213 (2000).

60.S. Dimmeler, A. Aicher, M. Vasa, C. Mildner-Rihm, K. Adler, M. Tiemann, H. Rutten,

S.Fichtlscherer, H. Martin and A. M. Zeiher, HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway, J. Clin. Invest. 108(3), 391-397 (2001).

61.J. Llevadot, S. Murasawa, Y. Kureishi, S. Uchida, H. Masuda, A. Kawamoto, K. Walsh,

J.M. Isner and T. Asahara, HMG-CoA reductase inhibitor mobilizes bone marrow-- derived endothelial progenitor cells, J. Clin. Invest. 108(3), 399-405 (2001).

62.S. Dimmeler and A. M. Zeiher, Akt takes center stage in angiogenesis signaling, Circ. Res. 86(1), 4-5 (2000).

63.Y. Kureishi, Z. Luo, I. Shiojima, A. Bialik, D. Fulton, D. J. Lefer, W. C. Sessa and

K.Walsh, The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals, Nat. Med. 6(9), 1004-1010 (2000).

64.M. Vasa, S. Fichtlscherer, A. Aicher, K. Adler, C. Urbich, H. Martin, A. M. Zeiher and

S.Dimmeler, Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease, Circ. Res. 89(1), E1-7 (2001).

65.B. P. Eliceiri and D. A. Cheresh, The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development, J. Clin. Invest. 103(9), 1227-1230 (1999).

66.J. M. Hill, G. Zalos, J. P. Halcox, W. H. Schenke, M. A. Waclawiw, A. A. Quyyumi and

T.Finkel, Circulating endothelial progenitor cells, vascular function, and cardiovascular risk, N. Engl. J. Med. 348(7), 593-600 (2003).

67.I. Ott, U. Keller, M. Knoedler, K. S. Gotze, K. Doss, P. Fischer, K. Urlbauer, G. Debus,

N.von Bubnoff, M. Rudelius, A. Schomig, C. Peschel and R. A. Oostendorp, Endothelial-like cells expanded from CD34+ blood cells improve left ventricular function after experimental myocardial infarction, Faseb J. 19(8), 992-994 (2005).

68.G. C. Schatteman, H. D. Hanlon, C. Jiao, S. G. Dodds and B. A. Christy, Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice, J. Clin. Invest. 106(4), 571-578 (2000).

69.K. Hirata, T. S. Li, M. Nishida, H. Ito, M. Matsuzaki, S. Kasaoka and K. Hamano, Autologous bone marrow cell implantation as therapeutic angiogenesis for ischemic hindlimb in diabetic rat model, Am. J. Physiol. Heart Circ. Physiol. 284(1), H66-70 (2003).

70.S. Ikenaga, K. Hamano, M. Nishida, T. Kobayashi, T. S. Li, S. Kobayashi, M. Matsuzaki,

N.Zempo and K. Esato, Autologous bone marrow implantation induced angiogenesis and improved deteriorated exercise capacity in a rat ischemic hindlimb model, J. Surg. Res. 96(2), 277-283 (2001).

71.A. Kawamoto, T. Tkebuchava, J. Yamaguchi, H. Nishimura, Y. S. Yoon, C. Milliken,

S.Uchida, O. Masuo, H. Iwaguro, H. Ma, A. Hanley, M. Silver, M. Kearney, D. W. Losordo,

J.M. Isner and T. Asahara, Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia, Circulation, 107(3), 461-468 (2003).

72.H. Kamihata, H. Matsubara, T. Nishiue, S. Fujiyama, Y. Tsutsumi, R. Ozono, H. Masaki,

Y.Mori, O. Iba, E. Tateishi, A. Kosaki, S. Shintani, T. Murohara, T. Imaizumi and

T.Iwasaka, Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines, Circulation, 104(9), 1046-1052 (2001).

73.C. Badorff, R. P. Brandes, R. Popp, S. Rupp, C. Urbich, A. Aicher, I. Fleming, R. Busse,

A.M. Zeiher and S. Dimmeler, Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes, Circulation, 107(7), 1024-1032 (2003).

74.E. Tateishi-Yuyama, H. Matsubara, T. Murohara, U. Ikeda, S. Shintani, H. Masaki,

K.Amano, Y. Kishimoto, K. Yoshimoto, H. Akashi, K. Shimada, T. Iwasaka and

T.Imaizumi, Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial, Lancet, 360(9331), 427-435 (2002).

75.B. Assmus, V. Schachinger, C. Teupe, M. Britten, R. Lehmann, N. Dobert, F. Grunwald,

A.Aicher, C. Urbich, H. Martin, D. Hoelzer, S. Dimmeler and A. M. Zeiher, Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI), Circulation, 106(24), 3009-3017 (2002).

76.B. E. Strauer, M. Brehm, T. Zeus, M. Kostering, A. Hernandez, R. V. Sorg, G. Kogler and P. Wernet, Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans, Circulation, 106(15), 1913-1918 (2002).

77.N. Dobert, M. Britten, B. Assmus, U. Berner, C. Menzel, R. Lehmann, N. Hamscho,

V.Schachinger, S. Dimmeler, A. M. Zeiher and F. Grunwald, Transplantation of progenitor cells after reperfused acute myocardial infarction: evaluation of perfusion and myocardial viability with FDG-PET and thallium SPECT, Eur. J. Nucl. Med. Mol. Imaging, 31(8), 1146-1151 (2004).

78.J. Aoki, P. W. Serruys, H. van Beusekom, A. T. Ong, E. P. McFadden, G. Sianos,

W.J. van der Giessen, E. Regar, P. J. de Feyter, H. R. Davis, S. Rowland and M. J. Kutryk, Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry, J. Am. Coll. Cardiol. 45(10), 1574-1579 (2005).

APPLICATIONS TO CLINICAL CONDITIONS

Chapter 19

RETINOPATHY OF PREMATURITY

Questions to Guide Molecular Biology

Dale L. Phelps

Departments of Pediatrics and Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, New York

1.INTRODUCTION

The explosion of knowledge on the development, maintenance, injury, and repair of the microvasculature leads to hope for the control of retinal neovascular diseases. Clinical disorders provide a framework on which to organize these data and our working hypotheses, as well as a very human reason to press on. Astute observations of the human disease and animal models guide investigations into mechanisms; in turn, understanding the mechanisms controlling vascular development and repair after injury leads to better treatment and control of the disease. This chapter describes retinopathy of prematurity (ROP), a particularly illuminating disease to study because it encompasses normal retinal vascular development, how it goes astray following premature birth, and the effects of several interventions.

363

J.S. Penn (ed.), Retinal and Choroidal Angiogenesis, 363–387.

© Springer Science+Business Media B.V. 2008

2.THE CLINICAL PICTURE OF ROP

2.1Epidemiology

In the United States, ROP affects about 2/3 of infants born weighing less than 1.25 kg (Figure 1A).1,2 Extrapolating from national statistics on rates of extremely low birth weight, close to 24,000 infants are born weighing less than 1.25 kg each year, and as their survival has risen3 (Figure 1B), more of the infants most likely to develop ROP are surviving each year. Fortunately, most cases of ROP do heal (regress) spontaneously, but between 8 and 17% of survivors will have sufficiently severe ROP to require surgery and will experience significant visual sequelae.4,5 Of those, an estimated 400-600 per year will have complete vision loss. While this may be a relatively small number, each represents a lifetime without vision: (500 cases)*(70 years) = 35,000 people-years of blindness added to our population each year.

Throughout developed countries, the problem is similar, and ROP is found primarily in infants weighing under 1.25 kg at birth. However, in developing countries where the technology of intensive care for preterm infants is just beginning to be provided, vision loss from ROP is higher, and there are few ophthalmologists able to perform examinations and treat the disease if it becomes severe. In these circumstances, infants of 1.25 to 2.5 kg can lose vision from ROP as well.8

2.2Clinical Course

At preterm birth, the retina shows no signs of disease, but is incompletely vascularized. Visible disease can rarely be detected with the indirect ophthalmoscope before 4 to 6 weeks after birth. Because the examinations cause some stress for the infant, they are usually delayed until then.1,9 ROP can be observed only by examining the retina, and indirect ophthalmoscopy must be carried out by experienced physicians, with wide-field fundus photography used as an adjunct.10 We’ve learned from animal models and autopsy data that the earliest phase of ROP pathophysiology begins soon after birth, but the vaso-obliteration associated with those changes is not visible then with our current instruments, particularly through the haze of the immature vitreous.