Semin Reprod Med 2009; 27(1): 080-089
DOI: 10.1055/s-0028-1108012
© Thieme Medical Publishers

Regulation of Angiogenesis in the Primate Endometrium: Vascular Endothelial Growth Factor

Krishna P. Chennazhi1 , Nihar R. Nayak1
  • 1Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
Further Information

Publication History

Publication Date:
05 February 2009 (online)

ABSTRACT

Unlike other tissues, endometrial vessels are unique because their functions are primarily orchestrated under the influence of ovarian steroid hormones, estradiol and progesterone. Although there is controversy in the literature on the expression of steroid hormone receptors in endometrial endothelial and vascular smooth muscle cells, it is believed that the actions of estradiol and progesterone are primarily mediated by paracrine interactions between the vascular and other cells of the endometrium. However, the regulatory mechanisms and local factors involved in mediating these paracrine interactions are not fully understood. Numerous angiogenic factors have been identified and implicated in endometrial vascular development and differentiation, but their relative contribution in endometrial angiogenesis is unknown. This review primarily focuses on the current progress in understanding the roles of a prototypical angiogenic factor, the vascular endothelial growth factor (VEGF), in the primate endometrium. Regulation of VEGF and its receptors in the endometrium appears to be highly complex, regulated by both steroid hormones as well as local factors independent of steroid hormones. The zone-specific and the cell-type specific expression of VEGF and its receptors in the endometrium suggest that steroid hormones likely regulate their expression through local cell-specific regulatory factors, rather than through direct gene transcription. Because VEGF receptors are expressed in both endothelial and nonendothelial cells, VEGF may have a pleiotropic role in this tissue. Recent development of highly potent VEGF inhibitors provides an opportunity to study the roles of VEGF in the primate endometrium. It is imperative that future studies focus on understanding specific roles of VEGF using these inhibitors, which is critically needed for development of new therapeutic strategies for numerous endometrial vascular disorders.

REFERENCES

  • 1 Hess A P, Nayak N R, Giudice L C. Oviduct and endometrium: cyclic changes in the primate oviduct and endometrium. In: Neill JD Knobil and Neill's Physiology of Reproduction. Vol. 1. New York, NY; Elsevier Science & Technology Books 2005: 337-381
  • 2 Brenner R M, Rudolph L, Matrisian L, Slayden O D. Non-human primate models; artificial menstrual cycles, endometrial matrix metalloproteinases and s.c. endometrial grafts.  Hum Reprod. 1996;  11(suppl 2) 150-164
  • 3 Markee J E. Menstruation in intraocular endometrial transplants in the rhesus monkey.  Contrib Embryol. 1940;  28 219-308
  • 4 Ramsey E M. Vascular anatomy. In: Wynn RM Biology of the Uterus. Volume 2. New York, NY; Plenum Press 1982: 59-76
  • 5 Bartelmez G W. The phases of the menstrual cycle and their interpretation in terms of the pregnancy cycle.  Am J Obstet Gynecol. 1957;  74(5) 931-955
  • 6 Rogers P A. Structure and function of endometrial blood vessels.  Hum Reprod Update. 1996;  2(1) 57-62
  • 7 Bartelmez G W. The form and functions of the uterine blood vessels in the rhesus monkey.  Contrib Embryol. 1957;  249 155-181
  • 8 Nayak N R, Brenner R M. Vascular proliferation and vascular endothelial growth factor expression in the rhesus macaque endometrium.  J Clin Endocrinol Metab. 2002;  87(4) 1845-1855
  • 9 Ferenczy A, Bertrand G, Gelfand M M. Proliferation kinetics of human endometrium during the normal menstrual cycle.  Am J Obstet Gynecol. 1979;  133(8) 859-867
  • 10 Rogers P A, Gargett C E. Endometrial angiogenesis.  Angiogenesis. 1998;  2(4) 287-294
  • 11 Goodger A M, Rogers P A. Endometrial endothelial cell proliferation during the menstrual cycle.  Hum Reprod. 1994;  9(3) 399-405
  • 12 Rogers P A, Abberton K M. Endometrial arteriogenesis: vascular smooth muscle cell proliferation and differentiation during the menstrual cycle and changes associated with endometrial bleeding disorders.  Microsc Res Tech. 2003;  60(4) 412-419
  • 13 Nayak N R, Kuo C J, Desai T A et al.. Expression, localization and hormonal control of angiopoietin-1 in the rhesus macaque endometrium: potential role in spiral artery growth.  Mol Hum Reprod. 2005;  11(11) 791-799
  • 14 Lubahn D B, Moyer J S, Golding T S, Couse J F, Korach K S, Smithies O. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene.  Proc Natl Acad Sci U S A. 1993;  90(23) 11162-11166
  • 15 Brenner R M, Slayden O D. Steroid receptors in blood vessels of the rhesus macaque endometrium: a review.  Arch Histol Cytol. 2004;  67(5) 411-416
  • 16 Iruela-Arispe M L, Rodriguez-Manzaneque J C, Abu-Jawdeh G. Endometrial endothelial cells express estrogen and progesterone receptors and exhibit a tissue specific response to angiogenic growth factors.  Microcirculation. 1999;  6(2) 127-140
  • 17 Press M F, Udove J A, Greene G L. Progesterone receptor distribution in the human endometrium. Analysis using monoclonal antibodies to the human progesterone receptor.  Am J Pathol. 1988;  131(1) 112-124
  • 18 Critchley H O, Brenner R M, Henderson T A et al.. Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium.  J Clin Endocrinol Metab. 2001;  86(3) 1370-1378
  • 19 Lecce G, Meduri G, Ancelin M, Bergeron C, Perrot-Applanat M. Presence of estrogen receptor beta in the human endometrium through the cycle: expression in glandular, stromal, and vascular cells.  J Clin Endocrinol Metab. 2001;  86(3) 1379-1386
  • 20 Krikun G, Schatz F, Taylor R et al.. Endometrial endothelial cell steroid receptor expression and steroid effects on gene expression.  J Clin Endocrinol Metab. 2005;  90(3) 1812-1818
  • 21 Silvestri A, Fraser H M. Oestrogen and progesterone receptors in the marmoset endometrium: changes during the ovulatory cycle, early pregnancy and after inhibition of vascular endothelial growth factor, GnRH or ovariectomy.  Reproduction. 2007;  134(2) 341-353
  • 22 Wehling M. Nongenomic aldosterone effects: the cell membrane as a specific target of mineralocorticoid action.  Steroids. 1995;  60(1) 153-156
  • 23 Simoncini T, Genazzani A R, Liao J K. Nongenomic mechanisms of endothelial nitric oxide synthase activation by the selective estrogen receptor modulator raloxifene.  Circulation. 2002;  105(11) 1368-1373
  • 24 Dvorak H F. Angiogenesis: update 2005.  J Thromb Haemost. 2005;  3(8) 1835-1842
  • 25 Carmeliet P. Angiogenesis in life, disease and medicine.  Nature. 2005;  438(7070) 932-936
  • 26 Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis.  Recent Prog Horm Res. 2000;  55 15-35 discussion 35-36
  • 27 Girling J E, Rogers P A. Recent advances in endometrial angiogenesis research.  Angiogenesis. 2005;  8(2) 89-99
  • 28 Risau W. Mechanisms of angiogenesis.  Nature. 1997;  386(6626) 671-674
  • 29 Asahara T, Masuda H, Takahashi T et al.. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization.  Circ Res. 1999;  85(3) 221-228
  • 30 Burri P H, Djonov V. Intussusceptive angiogenesis—the alternative to capillary sprouting.  Mol Aspects Med. 2002;  23(6S) S1-S27
  • 31 Hewett P, Nijjar S, Shams M, Morgan S, Gupta J, Ahmed A. Down-regulation of angiopoietin-1 expression in menorrhagia.  Am J Pathol. 2002;  160(3) 773-780
  • 32 Hirchenhain J, Huse I, Hess A, Bielfeld P, De Bruyne F, Krussel J S. Differential expression of angiopoietins 1 and 2 and their receptor Tie-2 in human endometrium.  Mol Hum Reprod. 2003;  9(11) 663-669
  • 33 Krikun G, Critchley H, Schatz F et al.. Abnormal uterine bleeding during progestin-only contraception may result from free radical-induced alterations in angiopoietin expression.  Am J Pathol. 2002;  161(3) 979-986
  • 34 Nelson K G, Takahashi T, Bossert N L, Walmer D K, McLachlan J A. Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation.  Proc Natl Acad Sci U S A. 1991;  88(1) 21-25
  • 35 Ferriani R A, Charnock-Jones D S, Prentice A, Thomas E J, Smith S K. Immunohistochemical localization of acidic and basic fibroblast growth factors in normal human endometrium and endometriosis and the detection of their mRNA by polymerase chain reaction.  Hum Reprod. 1993;  8(1) 11-16
  • 36 Samathanam C A, Adesanya O O, Zhou J, Wang J, Bondy C A. Fibroblast growth factors 1 and 2 in the primate uterus.  Biol Reprod. 1998;  59(3) 491-496
  • 37 Gold L I, Saxena B, Mittal K R et al.. Increased expression of transforming growth factor beta isoforms and basic fibroblast growth factor in complex hyperplasia and adenocarcinoma of the endometrium: evidence for paracrine and autocrine action.  Cancer Res. 1994;  54(9) 2347-2358
  • 38 Horowitz G M, Scott Jr R T, Drews M R, Navot D, Hofmann G E. Immunohistochemical localization of transforming growth factor-alpha in human endometrium, decidua, and trophoblast.  J Clin Endocrinol Metab. 1993;  76(3) 786-792
  • 39 Chegini N, Rossi M J, Masterson B J. Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and EGF and PDGF beta-receptors in human endometrial tissue: localization and in vitro action.  Endocrinology. 1992;  130(4) 2373-2385
  • 40 Yasuda Y, Masuda S, Chikuma M, Inoue K, Nagao M, Sasaki R. Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis.  J Biol Chem. 1998;  273(39) 25381-25387
  • 41 Zhao D, Li X P, Gao M, Zhao C, Wang J L, Wei L H. Stromal cell-derived factor 1alpha stimulates human endometrial carcinoma cell growth through the activation of both extracellular signal-regulated kinase 1/2 and Akt.  Gynecol Oncol. 2006;  103(3) 932-937
  • 42 Ahmed A, Dearn S. The role of platelet-activating factor and its receptor in endometrial receptivity.  Adv Exp Med Biol. 1996;  416 277-290
  • 43 Tsutsui J, Uehara K, Kadomatsu K, Matsubara S, Muramatsu T. A new family of heparin-binding factors: strong conservation of midkine (MK) sequences between the human and the mouse.  Biochem Biophys Res Commun. 1991;  176(2) 792-797
  • 44 Zhao Y, Hague S, Manek S, Zhang L, Bicknell R, Rees M C. PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium.  Oncogene. 1998;  16(3) 409-415
  • 45 Frater-Schroder M, Risau W, Hallmann R, Gautschi P, Bohlen P. Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo.  Proc Natl Acad Sci U S A. 1987;  84(15) 5277-5281
  • 46 Marsh M M, Hampton A L, Riley S C, Findlay J K, Salamonsen L A. Production and characterization of endothelin released by human endometrial epithelial cells in culture.  J Clin Endocrinol Metab. 1994;  79(6) 1625-1631
  • 47 Philippeaux M M, Piguet P F. Expression of tumor necrosis factor-alpha and its mRNA in the endometrial mucosa during the menstrual cycle.  Am J Pathol. 1993;  143(2) 480-486
  • 48 Tabibzadeh S, Kong Q F, Kapur S, Satyaswaroop P G, Aktories K. Tumour necrosis factor-alpha-mediated dyscohesion of epithelial cells is associated with disordered expression of cadherin/beta-catenin and disassembly of actin filaments.  Hum Reprod. 1995;  10(4) 994-1004
  • 49 Charnock-Jones D S, Sharkey A M, Rajput-Williams J et al.. Identification and localization of alternately spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines.  Biol Reprod. 1993;  48(5) 1120-1128
  • 50 Shifren J L, Tseng J F, Zaloudek C J et al.. Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis.  J Clin Endocrinol Metab. 1996;  81(8) 3112-3118
  • 51 Torry D S, Holt V J, Keenan J A, Harris G, Caudle M R, Torry R J. Vascular endothelial growth factor expression in cycling human endometrium.  Fertil Steril. 1996;  66(1) 72-80
  • 52 Ancelin M, Buteau-Lozano H, Meduri G et al.. A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus.  Proc Natl Acad Sci U S A. 2002;  99(9) 6023-6028
  • 53 Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G. Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165.  J Biol Chem. 2000;  275(24) 18040-18045
  • 54 Soker S, Miao H Q, Nomi M, Takashima S, Klagsbrun M. VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding.  J Cell Biochem. 2002;  85(2) 357-368
  • 55 Soker S, Takashima S, Miao H Q, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.  Cell. 1998;  92(6) 735-745
  • 56 Germeyer A, Hamilton A E, Laughlin L S et al.. Cellular expression and hormonal regulation of neuropilin-1 and -2 messenger ribonucleic acid in the human and rhesus macaque endometrium.  J Clin Endocrinol Metab. 2005;  90(3) 1783-1790
  • 57 Nayak N R, Critchley H O, Slayden O D et al.. Progesterone withdrawal up-regulates vascular endothelial growth factor receptor type 2 in the superficial zone stroma of the human and macaque endometrium: potential relevance to menstruation.  J Clin Endocrinol Metab. 2000;  85(9) 3442-3452
  • 58 Greb R R, Heikinheimo O, Williams R F, Hodgen G D, Goodman A L. Vascular endothelial growth factor in primate endometrium is regulated by oestrogen-receptor and progesterone-receptor ligands in vivo.  Hum Reprod. 1997;  12(6) 1280-1292
  • 59 Bausero P, Cavaille F, Meduri G, Freitas S, Perrot-Applanat M. Paracrine action of vascular endothelial growth factor in the human endometrium: production and target sites, and hormonal regulation.  Angiogenesis. 1998;  2(2) 167-182
  • 60 Li X F, Gregory J, Ahmed A. Immunolocalisation of vascular endothelial growth factor in human endometrium.  Growth Factors. 1994;  11(4) 277-282
  • 61 Punyadeera C, Thijssen V L, Tchaikovski S et al.. Expression and regulation of vascular endothelial growth factor ligands and receptors during menstruation and post-menstrual repair of human endometrium.  Mol Hum Reprod. 2006;  12(6) 367-375
  • 62 Taylor R N, Lebovic D I, Hornung D, Mueller M D. Endocrine and paracrine regulation of endometrial angiogenesis.  Ann N Y Acad Sci. 2001;  943 109-121
  • 63 Huang J C, Liu D Y, Dawood M Y. The expression of vascular endothelial growth factor isoforms in cultured human endometrial stromal cells and its regulation by 17beta-oestradiol.  Mol Hum Reprod. 1998;  4(6) 603-607
  • 64 Mueller M D, Vigne J L, Minchenko A, Lebovic D I, Leitman D C, Taylor R N. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta.  Proc Natl Acad Sci U S A. 2000;  97(20) 10972-10977
  • 65 Niklaus A L, Babischkin J S, Aberdeen G W, Pepe G J, Albrecht E D. Expression of vascular endothelial growth/permeability factor by endometrial glandular epithelial and stromal cells in baboons during the menstrual cycle and after ovariectomy.  Endocrinology. 2002;  143(10) 4007-4017
  • 66 Albrecht E D, Aberdeen G W, Niklaus A L, Babischkin J S, Suresch D L, Pepe G J. Acute temporal regulation of vascular endothelial growth/permeability factor expression and endothelial morphology in the baboon endometrium by ovarian steroids.  J Clin Endocrinol Metab. 2003;  88(6) 2844-2852
  • 67 Charnock-Jones D S, Macpherson A M, Archer D F et al.. The effect of progestins on vascular endothelial growth factor, oestrogen receptor and progesterone receptor immunoreactivity and endothelial cell density in human endometrium.  Hum Reprod. 2000;  15(suppl 3) 85-95
  • 68 Meduri G, Bausero P, Perrot-Applanat M. Expression of vascular endothelial growth factor receptors in the human endometrium: modulation during the menstrual cycle.  Biol Reprod. 2000;  62(2) 439-447
  • 69 Herve M A, Meduri G, Petit F G et al.. Regulation of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR by estradiol through VEGF in uterus.  J Endocrinol. 2006;  188(1) 91-99
  • 70 Sharkey A M, Day K, McPherson A et al.. Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia.  J Clin Endocrinol Metab. 2000;  85(1) 402-409
  • 71 Semenza G L. HIF-1: using two hands to flip the angiogenic switch.  Cancer Metastasis Rev. 2000;  19(1–2) 59-65
  • 72 Critchley H O, Osei J, Henderson T A et al.. Hypoxia-inducible factor-1alpha expression in human endometrium and its regulation by prostaglandin E-series prostanoid receptor 2 (EP2).  Endocrinology. 2006;  147(2) 744-753
  • 73 Popovici R M, Irwin J C, Giaccia A J, Giudice L C. Hypoxia and cAMP stimulate vascular endothelial growth factor (VEGF) in human endometrial stromal cells: potential relevance to menstruation and endometrial regeneration.  J Clin Endocrinol Metab. 1999;  84(6) 2245-2248
  • 74 Tuder R M, Flook B E, Voelkel N F. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide.  J Clin Invest. 1995;  95(4) 1798-1807
  • 75 Li J, Brown L F, Hibberd M G, Grossman J D, Morgan J P, Simons M. VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis.  Am J Physiol. 1996;  270(5 Pt 2) H1803-H1811
  • 76 Brogi E, Schatteman G, Wu T et al.. Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression.  J Clin Invest. 1996;  97(2) 469-476
  • 77 Gerber H P, Condorelli F, Park J, Ferrara N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia.  J Biol Chem. 1997;  272(38) 23659-23667
  • 78 Flamme I, Breier G, Risau W. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (flk-1) are expressed during vasculogenesis and vascular differentiation in the quail embryo.  Dev Biol. 1995;  169(2) 699-712
  • 79 Wang H, Keiser J A. Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells: role of flt-1.  Circ Res. 1998;  83(8) 832-840
  • 80 Singer A J, Clark R A. Cutaneous wound healing.  N Engl J Med. 1999;  341(10) 738-746
  • 81 Brown L F, Yeo K T, Berse B et al.. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing.  J Exp Med. 1992;  176(5) 1375-1379
  • 82 Peters K G, De Vries C, Williams L T. Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth.  Proc Natl Acad Sci U S A. 1993;  90(19) 8915-8919
  • 83 Frank S, Hubner G, Breier G, Longaker M T, Greenhalgh D G, Werner S. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing.  J Biol Chem. 1995;  270(21) 12607-12613
  • 84 Lauer G, Sollberg S, Cole M et al.. Expression and proteolysis of vascular endothelial growth factor is increased in chronic wounds.  J Invest Dermatol. 2000;  115(1) 12-18
  • 85 Howdieshell T R, Callaway D, Webb W L et al.. Antibody neutralization of vascular endothelial growth factor inhibits wound granulation tissue formation.  J Surg Res. 2001;  96(2) 173-182
  • 86 Jacobi J, Tam B Y, Sundram U et al.. Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis.  Gene Ther. 2004;  11(3) 302-309
  • 87 Brown L F, Detmar M, Claffey K et al.. Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine.  EXS. 1997;  79 233-269
  • 88 Gargett C E, Rogers P A. Human endometrial angiogenesis.  Reproduction. 2001;  121(2) 181-186
  • 89 Gargett C E, Lederman F L, Lau T M, Taylor N H, Rogers P A. Lack of correlation between vascular endothelial growth factor production and endothelial cell proliferation in the human endometrium.  Hum Reprod. 1999;  14(8) 2080-2088
  • 90 Goodger A M, Rogers P A, Affandi B. Endometrial endothelial cell proliferation in long-term users of subdermal levonorgestrel.  Hum Reprod. 1994;  9(9) 1647-1651
  • 91 Nayak N R, Brenner R M, Wiegand S J, Giudice L C. Blockade of vascular development in the rhesus macaque endometrium by treatment with VEGF-trap: role of VEGF in postmenstrual endometrial angiogenesis.  J Soc Gynecol Investig. 2004;  11(suppl) 186A
  • 92 Ferrara N, Kerbel R S. Angiogenesis as a therapeutic target.  Nature. 2005;  438(7070) 967-974

Nihar R Nayak

Department of Obstetrics and Gynecology, Stanford University School of Medicine

300 Pasteur Drive, HH-333, Stanford, CA 94305

Email: nayakn@stanford.edu

    >