{"paper_id":"3772abe5-1c07-4ab9-a489-d37ad7e429ad","body_text":"Abstract\nEndometriosis is a frequent gynecological disease, which is crucially dependent on the process of angiogenesis. However, the underlying regulatory mechanisms of blood vessel development are still poorly understood. CK2 is a pleiotropic protein kinase, which is implicated in the regulation of various cellular processes including angiogenesis. Herein we studied for the first time the function of protein kinase CK2 in angiogenesis of endometriotic lesions. For this purpose, we analyzed the anti-angiogenic activity of the CK2 inhibitor quinalizarin in a rat aortic ring assay and its effect on the expression of individual CK2 subunits and on kinase activity in endometrial tissue. Moreover, endometriotic lesions were induced in dorsal skinfold chambers of quinalizarin- and vehicle-treated C57BL/6 mice to study their vascularization and morphology by means of repetitive intravital fluorescence microscopy and histology. Our results demonstrate that quinalizarin dose-dependently inhibits vascular sprouting. In addition, treatment of endometrial tissue with quinalizarin reduces CK2 activity without affecting the expression of the three CK2 subunits α, α′ and β. In the dorsal skinfold chamber model of endometriosis, quinalizarin inhibits the vascularization of endometriotic lesions, which exhibit a significantly decreased vascularized area and functional capillary density when compared to those of vehicle-treated controls. This is associated with a reduced lesion size and histological fraction of endometrial glands. These findings indicate that CK2 is a regulator of angiogenesis in endometriotic lesions. Accordingly, inhibition of CK2 represents a novel option in the development of anti-angiogenic strategies for the treatment of endometriosis.\nSimilar content being viewed by others\nReferences\nViganò P, Parazzini F, Somigliana E, Vercellini P (2004) Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol 18:177–200\nGalle PC (1989) Clinical presentation and diagnosis of endometriosis. Obstet Gynecol Clin North Am 16:29–42\nSampson JA (1927) Peritoneal endometriosis due to menstrual dissemination of endometrial tissues into the peritoneal cavity. Am J Obstet Gynecol 14:422–469\nGargett CE, Masuda H (2010) Adult stem cells in the endometrium. Mol Hum Reprod 16:818–834\nMaruyama T, Masuda H, Ono M, Kajitani T, Yoshimura Y (2010) Human uterine stem/progenitor cells: their possible role in uterine physiology and pathology. Reproduction 140:11–22\nGroothuis PG, Nap AW, Winterhager E, Grümmer R (2005) Vascular development in endometriosis. Angiogenesis 8:147–156\nLaschke MW, Menger MD (2007) In vitro and in vivo approaches to study angiogenesis in the pathophysiology and therapy of endometriosis. Hum Reprod Update 13:331–342\nLaschke MW, Schwender C, Scheuer C, Vollmar B, Menger MD (2008) Epigallocatechin-3-gallate inhibits estrogen-induced activation of endometrial cells in vitro and causes regression of endometriotic lesions in vivo. Hum Reprod 23:2308–2318\nTaylor RN, Yu J, Torres PB, Schickedanz AC, Park JK, Mueller MD, Sidell N (2009) Mechanistic and therapeutic implications of angiogenesis in endometriosis. Reprod Sci 16:140–146\nMcLaren J (2000) Vascular endothelial growth factor and endometriotic angiogenesis. Hum Reprod Update 6:45–55\nTaylor RN, Lebovic DI, Mueller MD (2002) Angiogenic factors in endometriosis. Ann N Y Acad Sci 955:89–100\nFaust M, Montenarh M (2000) Subcellular localization of protein kinase CK2. A key to its function? Cell Tissue Res 301:329–340\nFaust M, Jung M, Günther J, Zimmermann R, Montenarh M (2001) Localization of individual subunits of protein kinase CK2 to the endoplasmic reticulum and to the Golgi apparatus. Mol Cell Biochem 227:73–80\nBibby AC, Litchfield DW (2005) The multiple personalities of the regulatory subunit of protein kinase CK2: CK2 dependent and CK2 independent roles reveal a secret identity for CK2 beta. Int J Biol Sci 1:67–79\nMontenarh M (2010) Cellular regulators of protein kinase CK2. Cell Tissue Res 342:139–146\nSt-Denis NA, Derksen DR, Litchfield DW (2009) Evidence for regulation of mitotic progression through temporal phosphorylation and dephosphorylation of CK2alpha. Mol Cell Biol 29:2068–2081\nLjubimov AV, Caballero S, Aoki AM, Pinna LA, Grant MB, Castellon R (2004) Involvement of protein kinase CK2 in angiogenesis and retinal neovascularization. Invest Ophthalmol Vis Sci 45:4583–4591\nKramerov AA, Saghizadeh M, Caballero S, Shaw LC, Li Calzi S, Bretner M, Montenarh M, Pinna LA, Grant MB, Ljubimov AV (2008) Inhibition of protein kinase CK2 suppresses angiogenesis and hematopoietic stem cell recruitment to retinal neovascularization sites. Mol Cell Biochem 316:177–186\nLaschke MW, Vorsterman van Oijen AE, Scheuer C, Menger MD (2011) In vitro and in vivo evaluation of the anti-angiogenic actions of 4-hydroxybenzyl alcohol. Br J Pharmacol 163:835–844\nEhrmantraut S, Laschke MW, Merkel D, Scheuer C, Willnecker V, Meyer-Lindenberg A, Menger MD, Naumann A (2010) Perioperative steroid administration inhibits angiogenic host tissue response to porous polyethylene (Medpor) implants. Eur Cell Mater 19:107–116\nFaust M, Schuster N, Montenarh M (1999) Specific binding of protein kinase CK2 catalytic subunits to tubulin. FEBS Lett 462:51–56\nSchuster N, Götz C, Faust M, Schneider E, Prowald A, Jungbluth A, Montenarh M (2001) Wild-type p53 inhibits protein kinase CK2 activity. J Cell Biochem 81:172–183\nNastainczyk W, Schmidt-Spaniol I, Boldyreff B, Issinger OG (1995) Isolation and characterization of a monoclonal anti-protein kinase CK2 beta-subunit antibody of the IgG class for the direct detection of CK2 beta-subunit in tissue cultures of various mammalian species and human tumors. Hybridoma 14:335–339\nLaschke MW, Elitzsch A, Vollmar B, Menger MD (2005) In vivo analysis of angiogenesis in endometriosis-like lesions by intravital fluorescence microscopy. Fertil Steril 84(Suppl 2):1199–1209\nLaschke MW, Elitzsch A, Scheuer C, Holstein JH, Vollmar B, Menger MD (2006) Rapamycin induces regression of endometriotic lesions by inhibiting neovascularization and cell proliferation. Br J Pharmacol 149:137–144\nMenger MD, Laschke MW, Vollmar B (2002) Viewing the microcirculation through the window: some twenty years experience with the hamster dorsal skinfold chamber. Eur Surg Res 34:83–91\nLaschke MW, Vollmar B, Menger MD (2011) The dorsal skinfold chamber: window into the dynamic interaction of biomaterials with their surrounding host tissue. Eur Cell Mater 22:147–164\nBaker M, Wayland H (1974) On-line volume flow rate and velocity profile measurement for blood in microvessels. Microvasc Res 7:131–143\nLitchfield DW (2003) Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J 369:1–15\nSchneider J, Huh MM, Bradlow HL, Fishman J (1984) Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J Biol Chem 259:4840–4845\nCozza G, Mazzorana M, Papinutto E, Bain J, Elliott M, di Maira G, Gianoncelli A, Pagano MA, Sarno S, Ruzzene M, Battistutta R, Meggio F, Moro S, Zagotto G, Pinna LA (2009) Quinalizarin as a potent, selective and cell-permeable inhibitor of protein kinase CK2. Biochem J 421:387–395\nMeng R, Götz C, Montenarh M (2010) The role of protein kinase CK2 in the regulation of the insulin production of pancreatic islets. Biochem Biophys Res Commun 401:203–206\nLawnicka H, Kowalewicz-Kulbat M, Sicinska P, Kazimierczuk Z, Grieb P, Stepien H (2010) Anti-neoplastic effect of protein kinase CK2 inhibitor, 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), on growth and hormonal activity of human adrenocortical carcinoma cell line (H295R) in vitro. Cell Tissue Res 340:371–379\nGrümmer R (2006) Animal models in endometriosis research. Hum Reprod Update 12:641–649\nKatayama H, Katayama T, Uematsu K, Hiratsuka M, Kiyomura M, Shimizu Y, Sugita A, Ito M (2010) Effect of dienogest administration on angiogenesis and hemodynamics in a rat endometrial autograft model. Hum Reprod 25:2851–2858\nLaschke MW, Elitzsch A, Vollmar B, Vajkoczy P, Menger MD (2006) 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 21:262–268\nNothnick WB (2010) Endometriosis: in search of optimal treatment. Minerva Ginecol 62:17–31\nKoga K, Takemura Y, Osuga Y, Yoshino O, Hirota Y, Hirata T, Morimoto C, Harada M, Yano T, Taketani Y (2006) Recurrence of ovarian endometrioma after laparoscopic excision. Hum Reprod 21:2171–2174\nGoel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK (2011) Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91:1071–1121\nReynolds LP, Killilea SD, Redmer DA (1992) Angiogenesis in the female reproductive system. FASEB J 6:886–892\nBecker CM, Beaudry P, Funakoshi T, Benny O, Zaslavsky A, Zurakowski D, Folkman J, D’Amato RJ, Ryeom S (2011) Circulating endothelial progenitor cells are up-regulated in a mouse model of endometriosis. Am J Pathol 178:1782–1791\nLaschke MW, Giebels C, Nickels RM, Scheuer C, Menger MD (2011) Endothelial progenitor cells contribute to the vascularization of endometriotic lesions. Am J Pathol 178:442–450\nLaschke MW, Giebels C, Menger MD (2011) Vasculogenesis: a new piece of the endometriosis puzzle. Hum Reprod Update 17:628–636\nAcknowledgments\nWe are grateful for the excellent technical assistance of Janine Becker from the Institute of Clinical and Experimental Surgery, Homburg/Saar, Germany.\nConflict of interest\nThe authors declare that they have no conflict of interest.\nEthical standards\nAll experiments of this study comply with the current laws of Germany. They were approved by the local governmental animal care committee and were conducted in accordance with the German legislation on protection of animals and the NIH Guidelines for the Care and Use of Laboratory Animals (NIH Publication #85-23 Rev. 1985).\nAuthor information\nAuthors and Affiliations\nCorresponding author\nRights and permissions\nAbout this article\nCite this article\nFeng, D., Welker, S., Körbel, C. et al. Protein kinase CK2 is a regulator of angiogenesis in endometriotic lesions. Angiogenesis 15, 243–252 (2012). https://doi.org/10.1007/s10456-012-9256-2\nReceived:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1007/s10456-012-9256-2","source_license":"public-domain-us","license_restricted":false}