Angiogenese im Corpus luteum des menstruellen Zyklus und der Frühgravidität

Zusammenfassung

Die Entwicklung eines normalen Gefäßsystems ist eine Voraussetzung für die Funktionsfähigkeit von Organen, da nur über die Blutbahn die Zellen mit Nährstoffen und Sauerstoff versorgt werden. Unter Vaskulogenese versteht man die Entwicklung der großen Stammgefäße im Organismus, die nur während der Embryonalperiode vorkommt, während Angiogenese als die Entwicklung neuer, abzweigender Kapillaren aus vorbestehenden Stammgefäßen definiert wird. Angiogenese findet auch später im ausgewachsenen Organismus vor allem bei Pathologien (Tumorangiogenese, Wundheilung, diabetische Retinopathie, Endometriose) statt. Ansonsten sind die meisten Organgefäßsysteme des Erwachsenen ausgereift, so dass aktive Angiogenese nicht mehr benötigt wird. Eine Ausnahme ist der weibliche Reproduktionstrakt. Als Besonderheit findet hier Angiogenese in monatlichen Zyklen statt, so dass eine übergeordnete hormonelle Kontrolle anzunehmen ist. Die Angiogenese und deren Regulation lassen sich vor allem während der Corpus-luteum-Entwicklung untersuchen, da hier innerhalb weniger Tage ein Organgefäßsystem entsteht, das eine hohe Durchblutung gewährleistet, so dass das Corpus luteum zu den am besten durchbluteten Organen des Organismus gehört. Der Blutfluss im Corpus luteum lässt sich mit malignen Tumoren vergleichen. Dieser Übersichtsartikel beschreibt die Physiologie der angiogenetischen Vorgänge im Corpus luteum und diskutiert die molekularen und hormonellen Regulationsmechanismen mit besonderem Schwerpunkt während der Frühgravidität.

Abstract

The development of a vascular system for the supply of oxygen and nutrients is a prerequisite for normal organ function. Angiogenesis is the development of new capillaries from pre-existing vessels. The vasculature of the adult is normally quiescent except under pathological conditions such as tumour angiogenesis or wound healing. However physiological angiogenesis occurs regularly in the female reproductive tract during the ovulatory cycle. Here, angiogenesis appears to be hormonally controlled. The corpus luteum is a site of intense angiogenesis and, when mature, has the highest blood supply of any organ in the body, which is comparable with malignant tumours. Within a short period, the development of the luteal vasculature is followed either by controlled regression of the microvascular tree in the non-fertile cycle, or by maintenance and stabilisation of the new vasculature in a conceptual cycle. This review focuses on the molecular and hormonal regulation of angiogenesis in the corpus luteum, especially during simulated pregnancy in the human.

Angiogenese - Corpus luteum - Gonadotropine - VEGF

Angiogenesis - corpus luteum - gonadotrophin - VEGF (vascular endothelial growth factor)

Literatur

• 1 Hanahan D. Signaling vascular morphogenesis and maintenance.  Science. 1997;  277 48-50
• 2 Fraser H M, Lunn S F. Angiogenesis and its control in the female reproductive system.  British Med Bull. 2000;  56 787-797
• 3 Fraser H M, Wulff C. Angiogenesis in the primate ovary.  Reproduction, Fertil Development. 2001;  13 557-566
• 4 Illingworth P J, Reddi K, Smith K, Baird D T. Pharmacologic “rescue” of the corpus luteum results in increased inhibin production.  Clin Endocrinol. 1990;  33 323-332
• 5 Suzuki T, Sasano H, TaKaya R, Fukaya T, Yajima A, Nagura H. Cyclic changes of vasculature and vascular phenotypes in normal human ovaries.  Hum Reprod. 1998;  13 953-959
• 6 Wulff C, Wiegand S J, Saunders P TK, Scobie G A, Fraser H M. Angiogenesis during follicular development and its inhibition by Flt-1-Fc (VEGF Trap_A40) in the primate.  Endocrinology. 2001;  142 3244-3254
• 7 Zeleznik A J, Schuleer H M, Reichert J RLE. Gonadotropin-binding sites in the rhesus monkey ovary: Role of the vasculature in the selective distribution of human chorionic gonadotropin to the preovulatory follicle.  Endocrinology. 1981;  109 356-362
• 8 Tsukada K, Matsushima T, Yamanaka N. Neovascularization of the corpus luteum of rats during the estrus cycle.  Pathology Int. 1996;  46 408-416
• 9 Augustin H G, Braun K, Telemenakis I, Modlich U, Kuhn W. Ovarian angiogenesis: Phenotypic characterization of endothelial cells in a physiological model of blood vessel growth and regression.  Am J Pathol. 1995;  147 339-351
• 10 Rodger F E, Young F M, Fraser H M, Illingworth P J. Endothelial cell proliferation follows the mid-cycle luteinizing hormone surge, but not human chorionic gonadotrophin rescue, in the human corpus luteum.  Hum Reprod. 1997;  12 1723-1729
• 11 Christenson L K, Stouffer R L. Proliferation of microvascular endothelial cells in the primate corpus luteum during the menstrual cycle and simulated early pregnancy.  Endocrinology. 1996;  137 367-374
• 12 Young F M, Rodger F E, Illingworth P J, Fraser H M. Cell proliferation and vascular morphology in the marmoset corpus luteum.  Hum Reprod. 2000;  15 557-566
• 13 Wulff C, Dickson S E, Duncan W C, Fraser H M. Angiogenesis in the human corpus luteum: Simulating early pregnancy by hCG treatment is associated with both angiogenesis and vessel stabilisation.  Hum Reprod. 2001;  16 2515-2524
• 14 Jablonka-Shariff A, Grazul-Bilska A T, Redmer D A, Reynolds L P. Growth and cellular proliferation of ovine corpora lutea throughout the estrous cycle.  Endocrinology. 1993;  133 1871-1879
• 15 Zheng J, Fricke P M, Reynolds L P, Redmer D A. Evaluation of growth, cell proliferation, and cell death in bovine corpora lutea throughout the estrous cycle.  Biol Reprod. 1994;  51 623-632
• 16 Al-Zi'abi M O, Watson E D, Fraser H M. Angiogenesis and vascular endothelial growth factor expression in the equine corpus luteum.  Reproduction. 2003;  125 259-270
• 17 Dickson S E, Fraser H M. Inhibition of early luteal angiogenesis by gonadotropin-releasing hormone antagonist treatment in the primate.  J Clin Endocrinol Metab. 2000;  85 2339-2344
• 18 Gaytan F, Morales C, Garcia-Pardo L, Reymundo C, Bellido C, Sanchez-Criado J. Macrophages, cell proliferation, and cell death in the human menstrual corpus luteum.  Biol Reprod. 1998;  59 417-425
• 19 Goede V, Schmidt T, Kimmina S, Kozian D, Augustin H G. Analysis of blood vessel maturation processes during cyclic ovarian angiogenesis.  Laboratory Invest. 1998;  78 1385-1394
• 20 Redmer D A, Doraiswamy V, Bortnem B J. et al . Evidence for a role of capillary pericytes in vascular growth of the developing ovine corpus luteum.  Biol Reprod. 2001;  65 879-889
• 21 Gale N W, Yancopoulos G D. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development.  Genes Dev. 1999;  13 1055-1066
• 22 Shalaby F, Rossant J, Yamaguchi T P. et al . Failure of blood-island formation and vasculogenesis in Flk-1 deficient mice.  Nature. 1995;  376 62-66
• 23 Fong G H, Rossant J, Gertsenstein M, Breitman M L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium.  Nature. 1995;  376 66-70
• 24 Sato E. Microvasculature in the mouse ovarian follicle demonstrated by a lectin angiography method.  Italian J Anatomy. 1995;  100 (Suppl 1) 461-467
• 25 Carmeliet P, Ferreira V, Breier G. et al . Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.  Nature. 1996;  380 435-439
• 26 Shweiki D, Itin A, Neufeld G, Gitay-Goren H, Keshet E. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis.  J Clin Invest. 1993;  91 2235-2243
• 27 Sharkey A M, Charnock-Jones D S, Boocock C A, Brown K D, Smith S K. Expression of mRNA for vascular endothelial growth factor in human placenta.  J Reprod Fertil. 1993;  99 609-615
• 28 Phillips H S, Hains J, Leung D W, Ferrara N. Vascular endothelial growth factor is expressed in rat corpus luteum.  Endocrinology. 1990;  127 965-967
• 29 Gordon J D, Mesiano S, Zaloudek C J, Jaffe R B. Vascular endothelial growth factor localization in human ovary and fallopian tubes: possible role in reproductive function and ovarian cyst formation.  J Clin Endocrinol Metab. 1996;  81 353-359
• 30 Otani N, Sawako M, Yamoto M. et al . The vascular endothelial growth factor/fms-like tyrosine kinase system in human ovary during the menstrual cycle and early pregnancy.  J Clin Endocrinol Metab. 1999;  84 3845-3851
• 31 Hazzard T M, Christenson L K, Stouffer R L. Changes in expression of vascular endothelial growth factor and angiopoietin-1 and -2 in the macaque corpus luteum during the menstrual cycle.  Mol Hum Reprod. 2000;  6 993-998
• 32 Wulff C, Wilson H, Largue P, Duncan W C, Armstrong D G, Fraser H M. Angiogenesis in the human corpus luteum: localization and changes in angiopoietins, Tie-2 and vascular endothelial growth factor messenger ribonucleic acid.  J Clin Endocrinol Metab. 2000;  85 4302-4309
• 33 Fraser H M, Wulff C, Wiegand S J, Rudge J S. Inhibition of vascular endothelial growth factor action in the primate reproductive system.  Biol Reprod. 2002;  66 (Suppl 1) 82
• 34 Wulff C, Wilson H, Rudge J S, Wiegand S J, Lunn S F, Fraser H M. Luteal angiogenesis: prevention or intervention by treatment with vascular endothelial growth factor Trap_A40.  J Clin Endocrinol Metab. 2001;  86 3377-3386
• 35 Davis S, Aldrich T H, Jones P F. et al . Isolation of Angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning.  Cell. 1996;  87 1161-1169
• 36 Suri C, Jones P, Patan S. et al . Requisite role of angiopoietin-1, a ligand for the Tie-2 receptor during embryonic angiogenesis.  Cell. 1996;  87 1171-1180
• 37 Maisonpierre P C, Suri C, Jones P F. et al . Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.  Science. 1997;  277 55-60
• 38 Ravindranath N, Little-Ihrig L, Phillips H S, Ferrara N, Zeleznik A J. Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary.  Endocrinology. 1992;  131 254-260
• 39 Redmer D A, Dai Y, Li J. et al . Characterization and expression of vascular endothelial growth factor (VEGF) in the ovine corpus luteum.  J Reprod Fertil. 1996;  108 157-165
• 40 Ravindranath N, Selvaraj N, Moudgal N R. Effects of selective deprivation of FSH and LH on follicular maturation in the bonnet monkey (Macaca radiata). . Moudgal NR, Yoshinaga K, Rao AJ, Adiga PR Perspectives in Primate Reproductive Biology. 1 ed. New Delhi; Wiley Eastern Limited 1991: 13-21
• 41 Christenson L K, Stouffer R L. Follicle-stimulating hormone and luteinizing hormone/chorionic gonadotropin stimulation of vascular endothelial growth factor production by macaque granulosa cells from pre- and periovulatory follicles.  J Clin Endocrinol Metab. 1997;  82 2135-2142
• 42 Neulen J, Raczek S, Pogorzelski M. et al . Secretion of vascular endothelial growth factor/vascular permeability factor from human luteinized granulosa cells is human chorionic gonadotrophin dependent.  Mol Hum Reprod. 1998;  4 203-206
• 43 Zygmunt M, Herr F, Keller-Schoenwetter S. et al . Characterization of human chorionic gonadotropin as a novel angiogenic factor.  J Clin Endocrinol Metab. 2002;  87 5290-5296
• 44 Neulen J, Yan Z P, Raczek S. et al . Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells: Importance in ovarian hyperstimulation syndrome.  J Clin Endocrinol Metab. 1995;  80 1967-1971
• 45 Rowe A J, Morris K D, Bicknell R, Fraser H M. Angiogenesis in the corpus luteum of early pregnancy in the marmoset and the effects of vascular endothelial growth factor immunoneutralization on establishment of pregnancy.  Biol Reprod. 2002;  67 1180-1188
• 46 Gaytan F, Morales C, Garcia-Pardo L. et al . A quantitative study of changes in the human corpus luteum microvasculature during the menstrual cycle.  Biol Reprod. 1999;  60 914-919
• 47 Wiegand S J, Boland P, Yancopoulos G D. Cooperative roles for the angiopoietins and vascular endothelial growth factor in ovarian angiogenesis. Adashi EY Ovulation: Evolving Scientific and Clinical Concepts. New York; Springer-Verlag 2000: 175-186
• 48 Findlay J K. Angiogenesis in reproductive tissues.  J Endocrinol. 1986;  111 357-366
• 49 Folkman J. Angiogenesis in female reproductive organs. Alexander NJ, D'Arcangues C Steroid Hormones and Uterine Bleeding. Washington DC; AAAS Press 1992: 143-158
• 50 Reynolds L P, Killilea S D, Redmer D A. Angiogenesis in the female reproductive system.  FASEB Journal. 1992;  6 886-892
• 51 Fraser H M, Dickson S E, Lunn S F. et al . Suppression of luteal angiogenesis in the primate by neutralization of vascular endothelial growth factor.  Endocrinology. 2000;  141 995-1000
• 52 Ferrara N, Chen H, Davis-Smyth T. et al . Vascular endothelial growth factor is essential for corpus luteum angiogenesis.  Nature Med. 1998;  4 336-340
• 53 Wulff C, Wilson H, Wiegand S J, Rudge J S, Fraser H M. Prevention of thecal angiogenesis, antral follicular growth and ovulation in the primate by treatment with endothelial growth factor trap R1R2.  Endocrinology. 2002;  143 2797-2807
• 54 Kamat B R, Brown L F, Manseau E J, Senger D R, Dvorak H F. Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells.  Am J Pathol. 1995;  146 157-165
• 55 Lee A, Burry K A, Christensen L K, Patton P E, Stouffer R L. Vascular endothelial growth factor levels in serum and follicular fluid of patients undergoing in vitro fertilization.  Fertil Steril. 1997;  68 305-311
• 56 Gescher D M, Meyhöfer-Malik A, Rath W, Malik E. mRNA-Expression von Angiopoietin-1 und -2 im ektopen Endometrium auf der Chorioallantoismembran (CAM).  Geburtsh Frauenheilk. 2003;  63 1279-1283