| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Pathology and Obstetrics and Gynecology (M.L.H., D.S.C.-J., C.L.K.C., S.K.S.) and Pharmacology (T.-P.D.F.), Reproductive Molecular Research Group, Cambridge, United Kingdom CB2 1QP; Women’s Reproductive Health Research Center, Vanderbilt University (K.L.B.-T., K.G.O.), Nashville, Tennessee 37232-2519; and Medical Research Council, Biostatistics Unit, Institute of Public Health (B.D.M.T.), Cambridge, United Kingdom CB2 2SR
Address all correspondence and requests for reprints to: Dr. Louise Hull, Departments of Pathology and Obstetrics and Gynecology, Reproductive Molecular Research Group, Tennis Court Road, Cambridge, United Kingdom CB2 1QP. E-mail: mlh30{at}cam.ac.uk.
Endometriosis is a disease in which the lining of the uterus (endometrium), shed at the time of menstruation, becomes established at sites such as the peritoneum and ovaries. These explants develop a rich blood supply that enables them to survive and grow. We hypothesized that inhibitors of angiogenesis would prevent this growth by disrupting sensitive vessels supplying endometriotic lesions. Vessels sensitive to angiogenic antagonism have few associations with pericyte cells. The vessels supplying human endometriotic lesions were immunohistochemically characterized and found to be predominantly pericyte free. A model in which human endometrium is implanted into nude mice was used to test the effects of two antagonists of the angiogenic growth factor, vascular endothelial cell growth factor A. Soluble truncated receptor (flt-1; P = 0.002) and an affinity-purified antibody to human vascular endothelial cell growth factor A (P = 0.03) significantly inhibited the growth of nude mouse explants. Pericyte-free vessels were shown to supply endometrial lesions in nude mice and were disrupted in lesions taken from soluble flt-1-treated mice. In summary, antiangiogenic agents inhibited the growth of explants in an in vivo model of endometriosis by disrupting the vascular supply, and this effect is likely to apply to the human disease. These findings suggest that antiangiogenic agents may provide a novel therapeutic approach for the treatment of endometriosis.
This work was supported by Medical Research Council Program Grant G9623012 and a grant from Pfizer Global Research and Development.
M.L.H. and D. S.C.-J. are joint first authors.
Abbreviations: bFGF, Basic fibroblast growth factor; CI, confidence interval; DAB, diaminobenzidine; FITC, fluorescein isothiocyanate; ITS, insulin-transferrin-selenium; Ig, immunoglobulin; sflt-1, soluble flt-1; 
SMA, anti-smooth muscle -actin; UEA-1, Ulex europaeus agglutinin-1; VEGF-A, vascular endothelial cell growth factor A; VEGFR, vascular endothelial cell growth factor receptor; vWF, von Willebrand factor.
This article has been cited by other articles:
 |
|
 |
|
  V. Monckedieck, C. Sannecke, B. Husen, M. Kumbartski, R. Kimmig, M. Totsch, E. Winterhager, and R. Grummer Progestins inhibit expression of MMPs and of angiogenic factors in human ectopic endometrial lesions in a mouse model Mol. Hum. Reprod., October 1, 2009; 15(10): 633 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. C. Ohlsson Teague, C. G. Print, and M. L. Hull The role of microRNAs in endometriosis and associated reproductive conditions Hum. Reprod. Update, September 22, 2009; (2009) dmp034v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-L. Alvarez Gonzalez, F. Frankenne, C. Galant, E. Marbaix, J.-M. Foidart, M. Nisolle, and A. Beliard Mixed origin of neovascularization of human endometrial grafts in immunodeficient mouse models Hum. Reprod., September 1, 2009; 24(9): 2217 - 2224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Shen, X. Liu, J.-G. Geng, and S.-W. Guo Increased Immunoreactivity to SLIT/ROBO1 in Ovarian Endometriomas: A Likely Constituent Biomarker for Recurrence Am. J. Pathol., August 1, 2009; 175(2): 479 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Bruner-Tran, K. G. Osteen, and A. J. Duleba Simvastatin Protects against the Development of Endometriosis in a Nude Mouse Model J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2489 - 2494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Novella-Maestre, C. Carda, I. Noguera, A. Ruiz-Sauri, J. A. Garcia-Velasco, C. Simon, and A. Pellicer Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis Hum. Reprod., May 1, 2009; 24(5): 1025 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. N. Taylor, Jie Yu, P. B. Torres, A. C. Schickedanz, J. K. Park, M. D. Mueller, and N. Sidell Mechanistic and Therapeutic Implications of Angiogenesis in Endometriosis Reproductive Sciences, February 1, 2009; 16(2): 140 - 146. [Abstract] [PDF]
|
|
|
|
 |
|
 A Martelli, N Bernabo, P Berardinelli, V Russo, C Rinaldi, O Di Giacinto, A Mauro, and B Barboni Vascular supply as a discriminating factor for pig preantral follicle selection Reproduction, January 1, 2009; 137(1): 45 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N.M. Nowak, O.M. Fischer, T.C. Gust, U. Fuhrmann, U.-F. Habenicht, and A. Schmidt Intraperitoneal inflammation decreases endometriosis in a mouse model Hum. Reprod., November 1, 2008; 23(11): 2466 - 2474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Laschke, C. Schwender, C. Scheuer, B. Vollmar, and M. D. Menger Epigallocatechin-3-gallate inhibits estrogen-induced activation of endometrial cells in vitro and causes regression of endometriotic lesions in vivo Hum. Reprod., October 1, 2008; 23(10): 2308 - 2318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Fraser, H. Wilson, A. Silvestri, K. D. Morris, and S. J. Wiegand The Role of Vascular Endothelial Growth Factor and Estradiol in the Regulation of Endometrial Angiogenesis and Cell Proliferation in the Marmoset Endocrinology, September 1, 2008; 149(9): 4413 - 4420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Hull, C. R. Escareno, J. M. Godsland, J. R. Doig, C. M. Johnson, S. C. Phillips, S. K. Smith, S. Tavare, C. G. Print, and D. S. Charnock-Jones Endometrial-Peritoneal Interactions during Endometriotic Lesion Establishment Am. J. Pathol., September 1, 2008; 173(3): 700 - 715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Defrere, J.C. Lousse, R. Gonzalez-Ramos, S. Colette, J. Donnez, and A. Van Langendonckt Potential involvement of iron in the pathogenesis of peritoneal endometriosis Mol. Hum. Reprod., July 1, 2008; 14(7): 377 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Van Langendonckt, J. Donnez, S. Defrere, G. A.J. Dunselman, and P. G. Groothuis Antiangiogenic and vascular-disrupting agents in endometriosis: pitfalls and promises Mol. Hum. Reprod., May 1, 2008; 14(5): 259 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Fainaru, A. Adini, O. Benny, I. Adini, S. Short, L. Bazinet, K. Nakai, E. Pravda, M. D. Hornstein, R. J. D'Amato, et al. Dendritic cells support angiogenesis and promote lesion growth in a murine model of endometriosis FASEB J, February 1, 2008; 22(2): 522 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Becker, N. Rohwer, T. Funakoshi, T. Cramer, W. Bernhardt, A. Birsner, J. Folkman, and R. J. D'Amato 2-Methoxyestradiol Inhibits Hypoxia-Inducible Factor-1{alpha} and Suppresses Growth of Lesions in a Mouse Model of Endometriosis Am. J. Pathol., February 1, 2008; 172(2): 534 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Zhang, N. Dmitrieva, Y. Liu, K. A. McGinty, and K. J. Berkley Endometriosis as a neurovascular condition: estrous variations in innervation, vascularization, and growth factor content of ectopic endometrial cysts in the rat Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R162 - R171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Van Langendonckt, C. Punyadeera, R. Kamps, G. Dunselman, L. Klein-Hitpass, L.J. Schurgers, J. Squifflet, J. Donnez, and P. Groothuis Identification of novel antigens in blood vessels in rectovaginal endometriosis Mol. Hum. Reprod., December 1, 2007; 13(12): 875 - 886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Sha, D. Wu, L. Zhang, X. Chen, M. Lei, H. Sun, S. Lin, and J. Lang Differentially expressed genes in human endometrial endothelial cells derived from eutopic endometrium of patients with endometriosis compared with those from patients without endometriosis Hum. Reprod., December 1, 2007; 22(12): 3159 - 3169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gilabert-Estelles, L.A. Ramon, F. Espana, J. Gilabert, V. Vila, E. Reganon, R. Castello, M. Chirivella, and A. Estelles Expression of angiogenic factors in endometriosis: relationship to fibrinolytic and metalloproteinase systems Hum. Reprod., August 1, 2007; 22(8): 2120 - 2127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Laschke and M. D. Menger In vitro and in vivo approaches to study angiogenesis in the pathophysiology and therapy of endometriosis Hum. Reprod. Update, July 1, 2007; 13(4): 331 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Oktem, I. Esinler, D. Eroglu, N. Haberal, N. Bayraktar, and H. B. Zeyneloglu High-dose atorvastatin causes regression of endometriotic implants: a rat model Hum. Reprod., May 1, 2007; 22(5): 1474 - 1480. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Masuda, T. Maruyama, E. Hiratsu, J. Yamane, A. Iwanami, T. Nagashima, M. Ono, H. Miyoshi, H. J. Okano, M. Ito, et al. Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/{gamma}Formula immunodeficient mice PNAS, February 6, 2007; 104(6): 1925 - 1930. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Roberts, L. K. Arbogast, C. I. Friedman, D. E. Cohn, P. T. Kaumaya, and D. R. Danforth Neutralization of Endogenous Vascular Endothelial Growth Factor Depletes Primordial Follicles in the Mouse Ovary Biol Reprod, February 1, 2007; 76(2): 218 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Grummer Animal models in endometriosis research Hum. Reprod. Update, September 1, 2006; 12(5): 641 - 649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Becker, R. D. Wright, R. Satchi-Fainaro, T. Funakoshi, J. Folkman, A. L. Kung, and R. J. D'Amato A Novel Noninvasive Model of Endometriosis for Monitoring the Efficacy of Antiangiogenic Therapy Am. J. Pathol., June 1, 2006; 168(6): 2074 - 2084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Bruner-Tran, Z. Zhang, E. Eisenberg, R. C. Winneker, and K. G. Osteen Down-Regulation of Endometrial Matrix Metalloproteinase-3 and -7 Expression in Vitro and Therapeutic Regression of Experimental Endometriosis in Vivo by a Novel Nonsteroidal Progesterone Receptor Agonist, Tanaproget J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1554 - 1560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Defrere, A. Van Langendonckt, R. G. Ramos, M. Jouret, M. Mettlen, and J. Donnez Quantification of endometriotic lesions in a murine model by fluorimetric and morphometric analyses Hum. Reprod., March 1, 2006; 21(3): 810 - 817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Lin, M.-D. Lai, H.-Y. Lei, and L.-Y. C. Wing Neutrophils and Macrophages Promote Angiogenesis in the Early Stage of Endometriosis in a Mouse Model Endocrinology, March 1, 2006; 147(3): 1278 - 1286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.W. Laschke, A. Elitzsch, B. Vollmar, P. Vajkoczy, and M.D. Menger Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, but not inhibition of VEGF alone, effectively suppresses angiogenesis and vessel maturation in endometriotic lesions Hum. Reprod., January 1, 2006; 21(1): 262 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bhanoori, K. Arvind Babu, N.G. Pavankumar Reddy, K. Lakshmi Rao, K. Zondervan, M. Deenadayal, S. Kennedy, and S. Shivaji The vascular endothelial growth factor (VEGF) +405G>C 5'-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study Hum. Reprod., July 1, 2005; 20(7): 1844 - 1849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Matsuura-Sawada, T. Murakami, Y. Ozawa, H. Nabeshima, J.-i. Akahira, Y. Sato, Y. Koyanagi, M. Ito, Y. Terada, and K. Okamura Reproduction of menstrual changes in transplanted human endometrial tissue in immunodeficient mice Hum. Reprod., June 1, 2005; 20(6): 1477 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. A. Harris, K. L. Bruner-Tran, X. Zhang, K. G. Osteen, and C. R. Lyttle A selective estrogen receptor-{beta} agonist causes lesion regression in an experimentally induced model of endometriosis Hum. Reprod., April 1, 2005; 20(4): 936 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.L. Hull, A. Prentice, D.Y. Wang, R.P. Butt, S.C. Phillips, S.K. Smith, and D.S. Charnock-Jones Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis Hum. Reprod., February 1, 2005; 20(2): 350 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Print, R. Valtola, A. Evans, K. Lessan, S. Malik, and S. Smith Soluble factors from human endometrium promote angiogenesis and regulate the endothelial cell transcriptome Hum. Reprod., October 1, 2004; 19(10): 2356 - 2366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ferrara Vascular Endothelial Growth Factor: Basic Science and Clinical Progress Endocr. Rev., August 1, 2004; 25(4): 581 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Berkley, N. Dmitrieva, K. S. Curtis, and R. E. Papka Innervation of ectopic endometrium in a rat model of endometriosis PNAS, July 27, 2004; 101(30): 11094 - 11098. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Van Langendonckt, F. Casanas-Roux, J. Eggermont, and J. Donnez Characterization of iron deposition in endometriotic lesions induced in the nude mouse model Hum. Reprod., June 1, 2004; 19(6): 1265 - 1271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Nap, A. W. Griffioen, G. A. J. Dunselman, J. C. A. Bouma-Ter Steege, V. L. J. L. Thijssen, J. L. H. Evers, and P. G. Groothuis Antiangiogenesis Therapy for Endometriosis J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1089 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Varma, T. Rollason, J. K Gupta, and E. R Maher Endometriosis and the neoplastic process Reproduction, March 1, 2004; 127(3): 293 - 304. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
