Este artículo es de Acceso Abierto y puede ser descargado en su versión final desde nuestro repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


The angiopoietin (ANGPT) receptor (TEK) system plays a crucial role in blood vessel development and regression. To date, no reports have addressed the actions of the anti-ANGPT1 antibody on gonadotropin-stimulated follicular development and atresia in the ovary. Therefore, in this study we specifically investigated whether ANGPT1 plays a critical intraovarian survival role for gonadotropin-dependent folliculogenesis. In particular, we examined the effect of local administration of anti-ANGPT1 antibody on follicular development, apoptosis, and expression of BCL2 protein family members (BAX, BCL2, and BCL2L1), TNFRSF6, and FASLG in ovarian follicles from prepubertal eCG-treated rats. The inhibition of ANGPT1 caused an increase in the number of atretic follicles and a decrease in the number of both antral follicles (AFs) and preovulatory follicles in gonadotropin-treated rat ovaries. Taking into account that follicular atresia is mediated by apoptosis, we analyzed the effect of the antibody against ANGPT1 on programmed cell death. The inhibition of the action of ANGPT1 caused an increase both in the number of apoptotic granulosa cells in AFs and in the spontaneous DNA fragmentation of AFs cultured in serum-free medium. Besides, AFs obtained from rats treated with intraovarian antibodies against ANGPT1 showed both a decrease in BCL2 and an increase in BAX protein levels. Moreover, a reduction in the BCL2L1L/BCL2L1S ratio was observed in this group, with a reduction of BCL2L1L greater than that of BCL2L1S, thus showing that the expression of these antiapoptotic proteins is lower in follicles from treated rats than in those from untreated ones. Our findings suggest that the inhibition of ANGPT1 activity causes an increase in the number of atretic follicles mediated by ovarian apoptosis through an imbalance in the ratio of antiapoptotic to proapoptotic proteins. This could take place through a paracrine effect on granulosa cells mediated by the TEK receptor in theca cells. Therefore, these data clearly indicate that ANGPT1 is necessary for follicular development induced by gonadotropins. © 2008 by the Society for the Study of Reproduction, Inc.


Documento: Artículo
Título:Intrabursal administration of the antiangiopoietin 1 antibody produces a delay in rat follicular development associated with an increase in ovarian apoptosis mediated by changes in the expression of BCL2 related genes
Autor:Parborell, F.; Abramovich, D.; Tesone, M.
Filiación:Instituto de Biología Y Medicina Experimental (IBYME)-CONICET, Facultad de Ciencias Exactas Y Naturales, Universidad de Buenos Aires (UBA), 1428 Buenos Aires, Argentina
Departamento de Química Biológica, Facultad de Ciencias Exactas Y Naturales, Universidad de Buenos Aires (UBA), 1428 Buenos Aires, Argentina
Palabras clave:Angiogenesis; Angiopoietin 1; Apoptosis; Follicle; Ovary; angiopoietin 1; angiopoietin 1 antibody; Fas antigen; Fas ligand; gonadotropin; inhibitor of apoptosis protein; protein antibody; protein Bax; protein bcl 2; protein bcl x; unclassified drug; angiogenesis; animal cell; animal experiment; animal model; apoptosis; article; cell culture; controlled study; culture medium; DNA fragmentation; gene expression; granulosa cell; nonhuman; ovary; ovary follicle; ovary follicle atresia; ovary follicle development; paracrine signaling; prepuberty; priority journal; protein blood level; protein expression; protein family; protein function; rat; theca cell; Angiopoietin-1; Animals; Antibodies; Apoptosis; Cell Count; DNA Fragmentation; Endothelium; Female; Gene Expression Regulation, Developmental; Gonadotropins; Injections, Intraperitoneal; Ovarian Follicle; Peritoneal Cavity; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Sexual Maturation; Rattus
Página de inicio:506
Página de fin:513
Título revista:Biology of Reproduction
Título revista abreviado:Biol. Reprod.
CAS:angiopoietin 1, 186270-49-5; gonadotropin, 63231-54-9; protein bcl 2, 219306-68-0; Angiopoietin-1; Antibodies; Gonadotropins; Proto-Oncogene Proteins c-bcl-2


  • Redmer, D.A., Reynolds, L.P., Angiogenesis in the ovary (1996) Rev Reprod, 1, pp. 182-192
  • Tamanini, C., De Ambrogi, M., Angiogenesis in developing follicle and corpus luteum (2004) Reprod Domest Anim, 39, pp. 206-216
  • Stouffer, R.L., Martinez-Chequer, J.C., Molskness, T.A., Xu, F., Hazzard, T.M., Regulation and action of angiogenic factors in the primate ovary (2001) Arch Med Res, 32, pp. 567-575
  • Maisonpierre, P.C., Suri, C., Jones, P.F., Bartunkova, S., Wiegand, S.J., Radziejewski, C., Compton, D., Davis, S., Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis (1997) Science, 277, pp. 55-60
  • Davis, S., Aldrich, T.H., Jones, P.F., Acheson, A., Compton, D.L., Jain, V., Ryan, T.E., Yancopoulos, G.D., Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning (1996) Cell, 87, pp. 1161-1169
  • Suri, C., Jones, P.F., Patan, S., Bartunkova, S., Maisonpierre, P.C., Davis, S., Sato, T.N., Yancopoulos, G.D., Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis (1996) Cell, 87, pp. 1171-1180
  • Hazzard, T.M., Molskness, T.A., Chaffin, C.L., Stouffer, R.L., Vascular endothelial growth factor (VEGF) and angiopoietin regulation by gonadotrophin and steroids in macaque granulosa cells during the periovulatory interval (1999) Mol Hum Reprod, 5, pp. 1115-1121
  • Wulff, C., Wiegand, S.J., Saunders, P.T., Scobie, G.A., Fraser, H.M., Angiogenesis during follicular development in the primate and its inhibition by treatment with truncated Flt-1-Fc (vascular endothelial growth factor Trap(A40)) (2001) Endocrinology, 142, pp. 3244-3254
  • Hayashi, K.G., Acosta, T.J., Tetsuka, M., Berisha, B., Matsui, M., Schams, D., Ohtani, M., Miyamoto, A., Involvement of angiopoietin-tie system in bovine follicular development and atresia: Messenger RNA expression in theca interna and effect on steroid secretion (2003) Biol Reprod, 69, pp. 2078-2084
  • Sugino, N., Suzuki, T., Sakata, A., Miwa, I., Asada, H., Taketani, T., Yamagata, Y., Tamura, H., Angiogenesis in the human corpus luteum: Changes in expression of angiopoietins in the corpus luteum throughout the menstrual cycle and in early pregnancy (2005) J Clin Endocrinol Metab, 90, pp. 6141-6148
  • Chun, S.Y., Eisenhauer, K.M., Minami, S., Hsueh, A.J., Growth factors in ovarian follicle atresia (1996) Semin Reprod Endocrinol, 14, pp. 197-202
  • Tilly, J.L., Kowalski, K.I., Johnson, A.L., Hsueh, A.J., Involvement of apoptosis in ovarian follicular atresia and postovulatory regression (1991) Endocrinology, 129, pp. 2799-2801
  • Tilly, J.L., Kowalski, K.I., Schomberg, D.W., Hsueh, A.J., Apoptosis in atretic ovarian follicles is associated with selective decreases in messenger ribonucleic acid transcripts for gonadotropin receptors and cytochrome P450 aromatase (1992) Endocrinology, 131, pp. 1670-1676
  • Tilly, J.L., Cell death and species propagation: Molecular and genetic aspects of apoptosis in the vertebrate female gonad (1998) When cells die: A comprehensive evaluation of apoptosis and programmed cell death, pp. 431-452. , Lockshin RA, Zakeri Z, Tilly JL eds, 1st ed. New York: Wiley-Liss;
  • Palumbo, A., Yeh, J., In situ localization of apoptosis in the rat ovary during follicular atresia (1994) Biol Reprod, 51, pp. 888-895
  • Gougeon, A., Regulation of ovarian follicular development in primates: Facts and hypotheses (1996) Endocr Rev, 17, pp. 121-155
  • Nahum, R., Beyth, Y., Chun, S.Y., Hsueh, A.J., Tsafriri, A., Early onset of deoxyribonucleic acid fragmentation during atresia of preovulatory ovarian follicles in rats (1996) Biol Reprod, 55, pp. 1075-1080
  • Tilly, J.L., Billig, H., Kowalski, K.I., Hsueh, A.J., Epidermal growth factor and basic fibroblast growth factor suppress the spontaneous onset of apoptosis in cultured rat ovarian granulosa cells and follicles by a tyrosine kinase-dependent mechanism (1992) Mol Endocrinol, 6, pp. 1942-1950
  • Chun, S.Y., Billig, H., Tilly, J.L., Furuta, I., Tsafriri, A., Hsueh, A.J., Gonadotropin suppression of apoptosis in cultured preovulatory follicles: Mediatory role of endogenous insulin-like growth factor I (1994) Endocrinology, 135, pp. 1845-1853
  • Tilly, J.L., Tilly, K.I., Inhibitors of oxidative stress mimic the ability of follicle-stimulating hormone to suppress apoptosis in cultured rat ovarian follicles (1995) Endocrinology, 136, pp. 242-252
  • McGee, E.A., Chun, S.Y., Lai, S., He, Y., Hsueh, A.J., Keratinocyte growth factor promotes the survival, growth, and differentiation of preantral ovarian follicles (1999) Fertil Steril, 71, pp. 732-738
  • Parborell, F., Dain, L., Tesone, M., Gonadotropin-releasing hormone agonist affects rat ovarian follicle development by interfering with FSH and growth factors on the prevention of apoptosis (2001) Mol Reprod Dev, 60, pp. 241-247
  • Tilly, J.L., Tilly, K.I., Kenton, M.L., Johnson, A.L., Expression of members of the bcl-2 gene family in the immature rat ovary: Equine chorionic gonadotropin-mediated inhibition of granulosa cell apoptosis is associated with decreased bax and constitutive bcl-2 and bcl-xlong messenger ribonucleic acid levels (1995) Endocrinology, 136, pp. 232-241
  • Hsu, S.Y., Hsueh, A.J., Tissue-specific Bcl-2 protein partners in apoptosis: An ovarian paradigm (2000) Physiol Rev, 80, pp. 593-614
  • Parborell, F., Pecci, A., Gonzalez, O., Vitale, A., Tesone, M., Effects of a gonadotropin-releasing hormone agonist on rat ovarian follicle apoptosis: Regulation by EGF and the expression of Bcl-2-related genes (2002) Biol Reprod, 67, pp. 481-486
  • Flaws, J.A., Kugu, K., Trbovich, A.M., DeSanti, A., Tilly, K.I., Hirshfield, A.N., Tilly, J.L., Interleukin-1 beta-converting enzyme-related proteases (IRPs) and mammalian cell death: Dissociation of IRP-induced oligonucleosomal endonuclease activity from morphological apoptosis in granulosa cells of the ovarian follicle (1995) Endocrinology, 136, pp. 5042-5053
  • Boone, D.L., Tsang, B.K., Caspase-3 in the rat ovary: Localization and possible role in follicular atresia and luteal regression (1998) Biol Reprod, 58, pp. 1533-1539
  • Hakuno, N., Koji, T., Yano, T., Kobayashi, N., Tsutsumi, O., Taketani, Y., Nakane, P.K., Fas/APO-1/CD95 system as a mediator of granulosa cell apoptosis in ovarian follicle atresia (1996) Endocrinology, 137, pp. 1938-1948
  • Kim, J.M., Yoon, Y.D., Tsang, B.K., Involvement of the Fas/Fas ligand system in p53-mediated granulosa cell apoptosis during follicular development and atresia (1999) Endocrinology, 140, pp. 2307-2317
  • Li, J., Kim, J.M., Liston, P., Li, M., Miyazaki, T., Mackenzie, A.E., Korneluk, R.G., Tsang, B.K., Expression of inhibitor of apoptosis proteins (IAPs) in rat granulosa cells during ovarian follicular development and atresia (1998) Endocrinology, 139, pp. 1321-1328
  • Woodruff, T.K., Lyon, R.J., Hansen, S.E., Rice, G.C., Mather, J.P., Inhibin and activin locally regulate rat ovarian folliculogenesis (1990) Endocrinology, 127, pp. 3196-3205
  • Andreu, C., Parborell, F., Vanzulli, S., Chemes, H., Tesone, M., Regulation of follicular luteinization by a gonadotropin-releasing hormone agonist: Relationship between steroidogenesis and apoptosis (1998) Mol Reprod Dev, 51, pp. 287-294
  • Sadrkhanloo, R., Hofeditz, C., Erickson, G.F., Evidence for widespread atresia in the hypophysectomized estrogen-treated rat (1987) Endocrinology, 120, pp. 146-155
  • Parborell, F., Irusta, G., Vitale, A.M., Gonzalez, O., Pecci, A., Tesone, M., GnRH antagonist Antide inhibits apoptosis of preovulatory follicle cells in rat ovary (2005) Biol Reprod, 72, pp. 659-666
  • D'Herde, K., De Pestel, G., Roels, F., In situ end labeling of fragmented DNA in induced ovarian atresia (1994) Biochem Cell Biol, 72, pp. 573-579
  • Rasband, W.S., ImageJ, U.S.,, Bethesda, Maryland. Available at:, November 29, 2006; Hughes Jr, F.M., Gorospe, W.C., Biochemical identification of apoptosis (programmed cell death) in granulosa cells: Evidence for a potential mechanism underlying follicular atresia (1991) Endocrinology, 129, pp. 2415-2422
  • Abramovich, D., Parborell, F., Tesone, M., Effect of a vascular endothelial growth factor (VEGF) inhibitory treatment on the folliculogenesis and ovarian apoptosis in gonadotropin-treated prepubertal rats (2006) Biol Reprod, 75, pp. 434-441
  • Taylor, P.D., Hillier, S.G., Fraser, H.M., Effects of GnRH antagonist treatment on follicular development and angiogenesis in the primate ovary (2004) J Endocrinol, 183, pp. 1-17
  • Gale, N.W., Thurston, G., Hackett, S.F., Renard, R., Wang, Q., McClain, J., Martin, C., Campochiaro, P.A., Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1 (2002) Dev Cell, 3, pp. 411-423
  • Xu, F., Hazzard, T.M., Evans, A., Charnock-Jones, S., Smith, S., Stouffer, R.L., Intraovarian actions of anti-angiogenic agents disrupt periovulatory events during the menstrual cycle in monkeys (2005) Contraception, 71, pp. 239-248
  • Quirk, S.M., Cowan, R.G., Joshi, S.G., Henrikson, K.P., Fas antigen-mediated apoptosis in human granulosa/luteal cells (1995) Biol Reprod, 52, pp. 279-287
  • Kondo, H., Maruo, T., Peng, X., Mochizuki, M., Immunological evidence for the expression of the Fas antigen in the infant and adult human ovary during follicular regression and atresia (1996) J Clin Endocrinol Metab, 81, pp. 2702-2710
  • Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993; 74:597-608; Oltvai, Z.N., Milliman, C.L., Korsmeyer, S.J., Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death (1993) Cell, 74, pp. 609-619
  • Valable, S., Bellail, A., Lesne, S., Liot, G., Mackenzie, E.T., Vivien, D., Bernaudin, M., Petit, E., Angiopoietin-1-induced PI3-kinase activation prevents neuronal apoptosis (2003) FASEB J, 17, pp. 443-445
  • Arai, F., Hirao, A., Ohmura, M., Sato, H., Matsuoka, S., Takubo, K., Ito, K., Suda, T., Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche (2004) Cell, 118, pp. 149-161


---------- APA ----------
Parborell, F., Abramovich, D. & Tesone, M. (2008) . Intrabursal administration of the antiangiopoietin 1 antibody produces a delay in rat follicular development associated with an increase in ovarian apoptosis mediated by changes in the expression of BCL2 related genes. Biology of Reproduction, 78(3), 506-513.
---------- CHICAGO ----------
Parborell, F., Abramovich, D., Tesone, M. "Intrabursal administration of the antiangiopoietin 1 antibody produces a delay in rat follicular development associated with an increase in ovarian apoptosis mediated by changes in the expression of BCL2 related genes" . Biology of Reproduction 78, no. 3 (2008) : 506-513.
---------- MLA ----------
Parborell, F., Abramovich, D., Tesone, M. "Intrabursal administration of the antiangiopoietin 1 antibody produces a delay in rat follicular development associated with an increase in ovarian apoptosis mediated by changes in the expression of BCL2 related genes" . Biology of Reproduction, vol. 78, no. 3, 2008, pp. 506-513.
---------- VANCOUVER ----------
Parborell, F., Abramovich, D., Tesone, M. Intrabursal administration of the antiangiopoietin 1 antibody produces a delay in rat follicular development associated with an increase in ovarian apoptosis mediated by changes in the expression of BCL2 related genes. Biol. Reprod. 2008;78(3):506-513.