This Article Full Text Full Text (PDF) A correction has been published Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lockwood, C. J. Articles by Schatz, F. Search for Related Content PubMed PubMed Citation Articles by Lockwood, C. J. Articles by Schatz, F.

Differential Effects of Thrombin and Hypoxia on Endometrial Stromal and Glandular Epithelial Cell Vascular Endothelial Growth Factor Expression

Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York 10016

Abstract

Ovarian steroids and/or premenstrual endometrial hypoxia are thought to restore the endometrial vasculature shed during menstruation by elevating endometrial vascular endothelial growth factor (VEGF) levels. During the luteal phase, VEGF levels peak, progesterone induces estradiol (E₂)-primed human endometrial stromal cells (HESCs) to decidualize and express tissue factor (TF), and endometrial vascular permeability is enhanced. The latter would present circulating clotting factors to decidual cell-expressed TF to form local thrombin. HESCs were incubated in serum-supplemented medium containing vehicle (control) or 10^-8 M E₂ or 10^-7 M medroxyprogesterone acetate (MPA) or E₂ + MPA for 7 d to induce decidualization, while monolayers of human endometrial glandular epithelial cells (HEGECs) formed during 4-d incubation of glands. The medium was exchanged for a defined medium containing corresponding vehicle or steroids ± thrombin under normoxia or hypoxia (0–1% O₂). Hypoxia enhanced secreted immunoreactive VEGF levels by severalfold in HESCs and HEGECs, but the steroids did not affect VEGF output in either cell type under normoxia or hypoxia. In E₂ + MPA-decidualized HESCs, VEGF levels were elevated by 0.1 U/ml of thrombin, and 0.5–2.5 U/ml of thrombin elicited maximum effects. The addition of 0.5 U/ml of thrombin evoked a time-dependent enhancement of VEGF levels and about an 8-fold increase at 48 h (P < 0.02; n = 6). Northern blotting indicated that E₂ + MPA-decidualized HESCs expressed VEGF₁₂₁, VEGF₁₆₅, and VEGF₁₈₉ mRNA, which were enhanced severalfold during 5- to 20-h incubation with thrombin. Moreover, TRAP, a synthetic peptide activator of the constitutively expressed protease activated receptor-1 thrombin receptor in decidualized HESCs, also elevated secreted VEGF levels. By contrast, HEGECs were unresponsive to thrombin added alone or with ovarian steroids. These results suggest that thrombin formed by progestin-augmented TF levels acts as an autocrine enhancer of VEGF expression in decidualized HESCs. Because angiogenesis occurs in a matrix of decidualized HESCs, these in vitro results provide a novel mechanism to account for both the peak in VEGF and angiogenesis in luteal phase human endometrium.

This article has been cited by other articles:

				C. J. Lockwood, G. Krikun, M. Hickey, S. J. Huang, and F. Schatz Decidualized Human Endometrial Stromal Cells Mediate Hemostasis, Angiogenesis, and Abnormal Uterine Bleeding Reproductive Sciences, February 1, 2009; 16(2): 162 - 170. [Abstract] [PDF]

				E. M MacDonald, A. Savoy, A. Gillgrass, S. Fernandez, M. Smieja, K. L Rosenthal, A. A Ashkar, and C. Kaushic Susceptibility of Human Female Primary Genital Epithelial Cells to Herpes Simplex Virus, Type-2 and the Effect of TLR3 Ligand and Sex Hormones on Infection Biol Reprod, December 1, 2007; 77(6): 1049 - 1059. [Abstract] [Full Text] [PDF]

				Z.-M. Bian, S. G. Elner, and V. M. Elner Thrombin-Induced VEGF Expression in Human Retinal Pigment Epithelial Cells Invest. Ophthalmol. Vis. Sci., June 1, 2007; 48(6): 2738 - 2746. [Abstract] [Full Text] [PDF]

				C. Punyadeera, V.L. Thijssen, S. Tchaikovski, R. Kamps, B. Delvoux, G.A.J. Dunselman, A.F.P.M. de Goeij, A.W. Griffioen, and P.G. Groothuis Expression and regulation of vascular endothelial growth factor ligands and receptors during menstruation and post-menstrual repair of human endometrium Mol. Hum. Reprod., June 1, 2006; 12(6): 367 - 375. [Abstract] [Full Text] [PDF]

				H. N. Jabbour, R. W. Kelly, H. M. Fraser, and H. O. D. Critchley Endocrine Regulation of Menstruation Endocr. Rev., February 1, 2006; 27(1): 17 - 46. [Abstract] [Full Text] [PDF]

				Y. Hirota, Y. Osuga, T. Hirata, O. Yoshino, K. Koga, M. Harada, C. Morimoto, E. Nose, T. Yano, O. Tsutsumi, et al. Possible Involvement of Thrombin/Protease-Activated Receptor 1 System in the Pathogenesis of Endometriosis J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3673 - 3679. [Abstract] [Full Text] [PDF]

				G. Krikun, F. Schatz, R. Taylor, H. O. D. Critchley, P. A. W. Rogers, J. Huang, and C. J. Lockwood Endometrial Endothelial Cell Steroid Receptor Expression and Steroid Effects on Gene Expression J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1812 - 1818. [Abstract] [Full Text] [PDF]

				G. Krikun, D. Sakkas, F. Schatz, L. Buchwalder, D. Hylton, C. Tang, and C. J. Lockwood Endometrial Angiopoietin Expression and Modulation by Thrombin and Steroid Hormones: A Mechanism for Abnormal Angiogenesis Following Long-Term Progestin-Only Contraception Am. J. Pathol., June 1, 2004; 164(6): 2101 - 2107. [Abstract] [Full Text] [PDF]

				C. J. Lockwood, P. Kumar, G. Krikun, S. Kadner, P. Dubon, H. Critchley, and F. Schatz Effects of Thrombin, Hypoxia, and Steroids on Interleukin-8 Expression in Decidualized Human Endometrial Stromal Cells: Implications for Long-Term Progestin-Only Contraceptive-Induced Bleeding J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1467 - 1475. [Abstract] [Full Text] [PDF]

				T. Minami, A. Sugiyama, S.-Q. Wu, R. Abid, T. Kodama, and W. C. Aird Thrombin and Phenotypic Modulation of the Endothelium Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 41 - 53. [Abstract] [Full Text] [PDF]

				G. Stratmann, I. A. Russell, and S. H. Merrick Use of recombinant factor VIIa as a rescue treatment for intractable bleeding following repeat aortic arch repair Ann. Thorac. Surg., December 1, 2003; 76(6): 2094 - 2097. [Abstract] [Full Text] [PDF]

				T. Kisliouk, N. Levy, A. Hurwitz, and R. Meidan Presence and Regulation of Endocrine Gland Vascular Endothelial Growth Factor/Prokineticin-1 and Its Receptors in Ovarian Cells J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3700 - 3707. [Abstract] [Full Text] [PDF]