Erythropoietin and Its Angiogenic Activity

Patrícia Kimáková, Peter Solár, Zuzana Solárová, Radovan Komel, Nataša Debeljak, Patrícia Kimáková, Peter Solár, Zuzana Solárová, Radovan Komel, Nataša Debeljak

Abstract

Erythropoietin (EPO) is the main hematopoietic hormone acting on progenitor red blood cells via stimulation of cell growth, differentiation, and anti-apoptosis. However, its receptor (EPOR) is also expressed in various non-hematopoietic tissues, including endothelium. EPO is a pleiotropic growth factor that exhibits growth stimulation and cell/tissue protection on numerous cells and tissues. In this article we review the angiogenesis potential of EPO on endothelial cells in heart, brain, and leg ischemia, as well as its role in retinopathy protection and tumor promotion. Furthermore, the effect of EPO on bone marrow and adipose tissue is also discussed.

Keywords: angiogenesis; cancer; endothelial; erythropoietin; erythropoietin receptor.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
EPO and the signalization of ECs. EPO-induced signalization of EC along with target genes associated with angiogenesis are outlined. Docking sites for several signaling proteins are marked with P; only positive interactions are presented with full black arrows. EPOR WikiPathway (Available on: http://www.wikipathways.org) was modified with PathVisio tool based on the references mentioned in the article.

References

    1. Jelkmann W. Erythropoietin: Structure, control of production, and function. Physiol. Rev. 1992;72:449–489.
    1. Lin C.S., Lim S.K., D’Agati V., Costantini F. Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev. 1996;10:154–164. doi: 10.1101/gad.10.2.154.
    1. Krantz S.B. Erythropoietin. Blood. 1991;77:419–434.
    1. Hardee M.E., Arcasoy M.O., Blackwell K.L., Kirkpatrick J.P., Dewhirst M.W. Erythropoietin biology in cancer. Clin. Cancer Res. 2006;12:332–339. doi: 10.1158/1078-0432.CCR-05-1771.
    1. Watowich S.S., Hilton D.J., Lodish H.F. Activation and inhibition of erythropoietin receptor function: Role of receptor dimerization. Mol. Cell. Biol. 1994;14:3535–3549. doi: 10.1128/MCB.14.6.3535.
    1. Pelekanou V., Kampa M., Kafousi M., Dambaki K., Darivianaki K., Vrekoussis T., Sanidas E., Tsiftsis D.D., Stathopoulos E.N., Castanas E. Erythropoietin and its receptor in breast cancer: Correlation with steroid receptors and outcome. Cancer Epidemiol. Biomark. Prev. 2007;16:2016–2023. doi: 10.1158/1055-9965.EPI-06-1023.
    1. Darnell J.E., Jr., Kerr I.M., Stark G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415–1421. doi: 10.1126/science.8197455.
    1. Janmaat M.L., Heerkens J.L., de Bruin A.M., Klous A., de Waard V., de Vries C.J. Erythropoietin accelerates smooth muscle cell-rich vascular lesion formation in mice through endothelial cell activation involving enhanced PDGF-BB release. Blood. 2010;115:1453–1460. doi: 10.1182/blood-2009-07-230870.
    1. Haller H., Christel C., Dannenberg L., Thiele P., Lindschau C., Luft F.C. Signal transduction of erythropoietin in endothelial cells. Kidney Int. 1996;50:481–488. doi: 10.1038/ki.1996.339.
    1. Carlini R.G., Dusso A.S., Obialo C.I., Alvarez U.M., Rothstein M. Recombinant human erythropoietin (rHuEPO) increases endothelin-1 release by endothelial cells. Kidney Int. 1993;43:1010–1014. doi: 10.1038/ki.1993.142.
    1. Carlini R.G., Reyes A.A., Rothstein M. Recombinant human erythropoietin stimulates angiogenesis in vitro. Kidney Int. 1995;47:740–745. doi: 10.1038/ki.1995.113.
    1. Anagnostou A., Lee E.S., Kessimian N., Levinson R., Steiner M. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc. Natl. Acad. Sci. USA. 1990;87:5978–5982. doi: 10.1073/pnas.87.15.5978.
    1. Anagnostou A., Liu Z., Steiner M., Chin K., Lee E.S., Kessimian N., Noguchi C.T. Erythropoietin receptor mRNA expression in human endothelial cells. Proc. Natl. Acad. Sci. USA. 1994;91:3974–3978. doi: 10.1073/pnas.91.9.3974.
    1. Noguchi C.T., Wang L., Rogers H.M., Teng R., Jia Y. Survival and proliferative roles of erythropoietin beyond the erythroid lineage. Expert Rev. Mol. Med. 2008;10:e36. doi: 10.1017/S1462399408000860.
    1. Heeschen C., Aicher A., Lehmann R., Fichtlscherer S., Vasa M., Urbich C., Mildner-Rihm C., Martin H., Zeiher A.M., Dimmeler S. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood. 2003;102:1340–1346. doi: 10.1182/blood-2003-01-0223.
    1. Santhanam A.V., d’Uscio L.V., Peterson T.E., Katusic Z.S. Activation of endothelial nitric oxide synthase is critical for erythropoietin-induced mobilization of progenitor cells. Peptides. 2008;29:1451–1455. doi: 10.1016/j.peptides.2008.03.016.
    1. Westenbrink B.D., Lipsic E., van der Meer P., van der Harst P., Oeseburg H., Du Marchie Sarvaas G.J., Koster J., Voors A.A., van Veldhuisen D.J., van Gilst W.H., et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur. Heart J. 2007;28:2018–2027. doi: 10.1093/eurheartj/ehm177.
    1. Brines M., Cerami A. Discovering erythropoietin’s extra-hematopoietic functions: Biology and clinical promise. Kidney Int. 2006;70:246–250. doi: 10.1038/sj.ki.5001546.
    1. Yang J., Xiao Z., Li T., Gu X., Fan B. Erythropoietin promotes the growth of pituitary adenomas by enhancing angiogenesis. Int. J. Oncol. 2012;40:1230–1237.
    1. Kawachi K., Iso Y., Sato T., Wakabayashi K., Kobayashi Y., Takeyama Y., Suzuki H. Effects of erythropoietin on angiogenesis after myocardial infarction in porcine. Heart Vessel. 2012;27:79–88. doi: 10.1007/s00380-011-0197-2.
    1. Ahn S., Min S.K., Min S.I., Suh J.H., Kim S.J., Ha J. Early sustained injections of erythropoietin improve angiogenesis and restoration of perfusion in the ischemic mouse hindlimb. J. Korean Med. Sci. 2012;27:1073–1078. doi: 10.3346/jkms.2012.27.9.1073.
    1. Ribatti D., Presta M., Vacca A., Ria R., Giuliani R., Dell’Era P., Nico B., Roncali L., Dammacco F. Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood. 1999;93:2627–2636.
    1. Yamaji R., Okada T., Moriya M., Naito M., Tsuruo T., Miyatake K., Nakano Y. Brain capillary endothelial cells express two forms of erythropoietin receptor mRNA. Eur. J. Biochem. 1996;239:494–500. doi: 10.1111/j.1432-1033.1996.0494u.x.
    1. Hu D.E., Hiley C.R., Fan T.P. Comparative studies of the angiogenic activity of vasoactive intestinal peptide, endothelins-1 and -3 and angiotensin II in a rat sponge model. Br. J. Pharmacol. 1996;117:545–551. doi: 10.1111/j.1476-5381.1996.tb15225.x.
    1. Ashley R.A., Dubuque S.H., Dvorak B., Woodward S.S., Williams S.K., Kling P.J. Erythropoietin stimulates vasculogenesis in neonatal rat mesenteric microvascular endothelial cells. Pediatr. Res. 2002;51:472–478. doi: 10.1203/00006450-200204000-00012.
    1. Alvarez Arroyo M.V., Castilla M.A., Gonzalez Pacheco F.R., Tan D., Riesco A., Casado S., Caramelo C. Role of vascular endothelial growth factor on erythropoietin-related endothelial cell proliferation. J. Am. Soc. Nephrol. 1998;9:1998–2004.
    1. Beleslin-Cokic B.B., Cokic V.P., Yu X., Weksler B.B., Schechter A.N., Noguchi C.T. Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood. 2004;104:2073–2080. doi: 10.1182/blood-2004-02-0744.
    1. Casas A., Di Venosa G., Hasan T., Al B. Mechanisms of resistance to photodynamic therapy. Curr. Med. Chem. 2011;18:2486–2515. doi: 10.2174/092986711795843272.
    1. Yu Y.B., Su K.H., Kou Y.R., Guo B.C., Lee K.I., Wei J., Lee T.S. Role of transient receptor potential vanilloid 1 in regulating erythropoietin-induced activation of endothelial nitric oxide synthase. Acta Physiol. 2016;219:465–477. doi: 10.1111/apha.12723.
    1. Xiao J.W., Li L.H., Hong B.Z., Xiao J.Q., Wei D.M., Jin Z. Therapeutic effects and related mechanisms of erythropoietin sustained-release gelatin hydrogel microspheres on a murine model of hindlimb ischemia. Zhonghua Xin Xue Guan Bing Za Zhi. 2016;44:524–529.
    1. Su K.H., Shyue S.K., Kou Y.R., Ching L.C., Chiang A.N., Yu Y.B., Chen C.Y., Pan C.C., Lee T.S. β Common receptor integrates the erythropoietin signaling in activation of endothelial nitric oxide synthase. J. Cell. Physiol. 2011;226:3330–3339. doi: 10.1002/jcp.22678.
    1. Lamanuzzi A., Saltarella I., Ferrucci A., Ria R., Ruggieri S., Racanelli V., Rao L., Annese T., Nico B., Vacca A., Ribatti D. Role of erythropoietin in the angiogenic activity of bone marrow endothelial cells of MGUS and multiple myeloma patients. Oncotarget. 2016;7:14510–14521.
    1. De Luisi A., Binetti L., Ria R., Ruggieri S., Berardi S., Catacchio I., Racanelli V., Pavone V., Rossini B., Vacca A., Ribatti D. Erythropoietin is involved in the angiogenic potential of bone marrow macrophages in multiple myeloma. Angiogenesis. 2013;16:963–973. doi: 10.1007/s10456-013-9369-2.
    1. Su J., Li Z., Cui S., Ji L., Geng H., Chai K., Ma X., Bai Z., Yang Y., Wuren T., Ge R.L., Rondina M.T. The local HIF-2α/EPO pathway in the bone marrow is associated with excessive erythrocytosis and the increase in bone marrow microvessel density in chronic mountain sickness. High Alt. Med. Biol. 2015;16:318–330. doi: 10.1089/ham.2015.0015.
    1. Wan L., Zhang F., He Q., Tsang W.P., Lu L., Li Q., Wu Z., Qiu G., Zhou G., Wan C. EPO promotes bone repair through enhanced cartilaginous callus formation and angiogenesis. PLoS ONE. 2014;9:e102010. doi: 10.1371/journal.pone.0102010.
    1. Holstein J.H., Orth M., Scheuer C., Tami A., Becker S.C., Garcia P., Histing T., Morsdorf P., Klein M., Pohlemann T., Menger M.D. Erythropoietin stimulates bone formation, cell proliferation, and angiogenesis in a femoral segmental defect model in mice. Bone. 2011;49:1037–1045. doi: 10.1016/j.bone.2011.08.004.
    1. Luk C.T., Shi S.Y., Choi D., Cai E.P., Schroer S.A., Woo M. In vivo knockdown of adipocyte erythropoietin receptor does not alter glucose or energy homeostasis. Endocrinology. 2013;154:3652–3659. doi: 10.1210/en.2013-1113.
    1. Mikolas E., Cseh J., Pap M., Szijarto I.A., Balogh A., Laczy B., Beko V., Fisi V., Molnar G.A., Merei A., et al. Effects of erythropoietin on glucose metabolism. Horm Metab. Res. 2012;44:279–285. doi: 10.1055/s-0032-1301901.
    1. Hamed S., Egozi D., Kruchevsky D., Teot L., Gilhar A., Ullmann Y. Erythropoietin improves the survival of fat tissue after its transplantation in nude mice. PLoS ONE. 2010;5:e13986. doi: 10.1371/journal.pone.0013986.
    1. Elsherbiny A., Hogger D.C., Borozadi M.K., Schmidt C.A., Plock J., Largo R.D., Lindenblatt N., Giovanoli P., Contaldo C. EPO reverses defective wound repair in hypercholesterolaemic mice by increasing functional angiogenesis. J. Plast. Reconstr. Aesthet. Surg. 2012;65:1559–1568. doi: 10.1016/j.bjps.2012.05.006.
    1. Teng R., Gavrilova O., Suzuki N., Chanturiya T., Schimel D., Hugendubler L., Mammen S., Yver D.R., Cushman S.W., Mueller E., et al. Disrupted erythropoietin signalling promotes obesity and alters hypothalamus proopiomelanocortin production. Nat. Commun. 2001;2:520. doi: 10.1038/ncomms1526.
    1. Westenbrink B.D., Oeseburg H., Kleijn L., van der Harst P., Belonje A.M., Voors A.A., Schoemaker R.G., de Boer R.A., van Veldhuisen D.J., van Gilst W.H. Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia. Cardiovasc. Drugs Ther. 2008;22:265–274. doi: 10.1007/s10557-008-6094-y.
    1. Imamura R., Moriyama T., Isaka Y., Namba Y., Ichimaru N., Takahara S., Okuyama A. Erythropoietin protects the kidneys against ischemia reperfusion injury by activating hypoxia inducible factor-1α. Transplantation. 2007;83:1371–1379. doi: 10.1097/01.tp.0000264200.38926.70.
    1. Wang L., Zhang Z., Wang Y., Zhang R., Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004;35:1732–1737. doi: 10.1161/01.STR.0000132196.49028.a4.
    1. Nakano M., Satoh K., Fukumoto Y., Ito Y., Kagaya Y., Ishii N., Sugamura K., Shimokawa H. Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ. Res. 2007;100:662–669. doi: 10.1161/01.RES.0000260179.43672.fe.
    1. Zentilin L., Tafuro S., Zacchigna S., Arsic N., Pattarini L., Sinigaglia M., Giacca M. Bone marrow mononuclear cells are recruited to the sites of VEGF-induced neovascularization but are not incorporated into the newly formed vessels. Blood. 2006;107:3546–3554. doi: 10.1182/blood-2005-08-3215.
    1. Satoh K., Fukumoto Y., Nakano M., Kagaya Y., Shimokawa H. Emergence of the erythropoietin/erythropoietin receptor system as a novel cardiovascular therapeutic target. J. Cardiovasc. Pharmacol. 2011;58:570–574. doi: 10.1097/FJC.0b013e318235e7bb.
    1. Sanchis-Gomar F., Garcia-Gimenez J.L., Pareja-Galeano H., Romagnoli M., Perez-Quilis C., Lippi G. Erythropoietin and the heart: Physiological effects and the therapeutic perspective. Int. J. Cardiol. 2014;171:116–125. doi: 10.1016/j.ijcard.2013.12.011.
    1. Kobayashi H., Miura T., Ishida H., Miki T., Tanno M., Yano T., Sato T., Hotta H., Shimamoto K. Limitation of infarct size by erythropoietin is associated with translocation of AKT to the mitochondria after reperfusion. Clin. Exp. Pharmacol. Physiol. 2008;35:812–819. doi: 10.1111/j.1440-1681.2008.04925.x.
    1. Hu X., Yu S.P., Fraser J.L., Lu Z., Ogle M.E., Wang J.A., Wei L. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J. Thorac. Cardiovasc. Surg. 2008;135:799–808. doi: 10.1016/j.jtcvs.2007.07.071.
    1. Lu J., Yao Y.Y., Dai Q.M., Ma G.S., Zhang S.F., Cao L., Ren L.Q., Liu N.F. Erythropoietin attenuates cardiac dysfunction by increasing myocardial angiogenesis and inhibiting interstitial fibrosis in diabetic rats. Cardiovasc. Diabetol. 2012;11:105. doi: 10.1186/1475-2840-11-105.
    1. Joshi D., Tsui J., Ho T.K., Selvakumar S., Abraham D.J., Baker D.M. Review of the role of erythropoietin in critical leg ischemia. Angiology. 2010;61:541–550. doi: 10.1177/0003319709358697.
    1. Bennis Y., Sarlon-Bartoli G., Guillet B., Lucas L., Pellegrini L., Velly L., Blot-Chabaud M., Dignat-Georges F., Sabatier F., Pisano P. Priming of late endothelial progenitor cells with erythropoietin before transplantation requires the CD131 receptor subunit and enhances their angiogenic potential. J. Thromb. Haemost. 2012;10:1914–1928. doi: 10.1111/j.1538-7836.2012.04835.x.
    1. Li H.G., Li J.S., Chen W.L., Wang L., Wu D.H., Lin Z.Y. Prognostic significance of erythropoietin and erythropoietin receptor in tongue squamous cell carcinoma. Br. J. Oral Maxillofac. Surg. 2009;47:470–475. doi: 10.1016/j.bjoms.2009.06.001.
    1. Yu J., deMuinck E.D., Zhuang Z., Drinane M., Kauser K., Rubanyi G.M., Qian H.S., Murata T., Escalante B., Sessa W.C. Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve. Proc. Natl. Acad. Sci. USA. 2005;102:10999–11004. doi: 10.1073/pnas.0501444102.
    1. Kupatt C., Hinkel R., von Bruhl M.L., Pohl T., Horstkotte J., Raake P., El Aouni C., Thein E., Dimmeler S., Feron O., et al. Endothelial nitric oxide synthase overexpression provides a functionally relevant angiogenic switch in hibernating pig myocardium. J. Am. Coll. Cardiol. 2007;49:1575–1584. doi: 10.1016/j.jacc.2006.11.047.
    1. Kato S., Amano H., Ito Y., Eshima K., Aoyama N., Tamaki H., Sakagami H., Satoh Y., Izumi T., Majima M. Effect of erythropoietin on angiogenesis with the increased adhesion of platelets to the microvessels in the hind-limb ischemia model in mice. J. Pharmacol. Sci. 2010;112:167–175. doi: 10.1254/jphs.09262FP.
    1. Chen J., Connor K.M., Aderman C.M., Smith L.E. Erythropoietin deficiency decreases vascular stability in mice. J. Clin. Investig. 2008;118:526–533. doi: 10.1172/JCI33813.
    1. Grant M.B., May W.S., Caballero S., Brown G.A., Guthrie S.M., Mames R.N., Byrne B.J., Vaught T., Spoerri P.E., Peck A.B., et al. Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat. Med. 2002;8:607–612. doi: 10.1038/nm0602-607.
    1. Otani A., Kinder K., Ewalt K., Otero F.J., Schimmel P., Friedlander M. Bone marrow-derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis. Nat. Med. 2002;8:1004–1010. doi: 10.1038/nm744.
    1. Ritter M.R., Banin E., Moreno S.K., Aguilar E., Dorrell M.I., Friedlander M. Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy. J. Clin. Investig. 2006;116:3266–3276. doi: 10.1172/JCI29683.
    1. Checchin D., Sennlaub F., Levavasseur E., Leduc M., Chemtob S. Potential role of microglia in retinal blood vessel formation. Investig. Ophthalmol. Vis. Sci. 2006;47:3595–3602. doi: 10.1167/iovs.05-1522.
    1. Watanabe D., Suzuma K., Matsui S., Kurimoto M., Kiryu J., Kita M., Suzuma I., Ohashi H., Ojima T., Murakami T., et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N. Engl. J. Med. 2005;353:782–792. doi: 10.1056/NEJMoa041773.
    1. Chen J., Connor K.M., Aderman C.M., Willett K.L., Aspegren O.P., Smith L.E. Suppression of retinal neovascularization by erythropoietin siRNA in a mouse model of proliferative retinopathy. Investig. Ophthalmol. Vis. Sci. 2009;50:1329–1335. doi: 10.1167/iovs.08-2521.
    1. Eldweik L., Mantagos I.S. Role of VEGF inhibition in the treatment of retinopathy of prematurity. Semin. Ophthalmol. 2016;31:163–168. doi: 10.3109/08820538.2015.1114847.
    1. Van Wijngaarden P., Brereton H.M., Gibbins I.L., Coster D.J., Williams K.A. Kinetics of strain-dependent differential gene expression in oxygen-induced retinopathy in the rat. Exp. Eye Res. 2007;85:508–517. doi: 10.1016/j.exer.2007.07.001.
    1. Caprara C., Britschgi C., Samardzija M., Grimm C. The erythropoietin receptor is not required for the development, function, and aging of rods and cells in the retinal periphery. Mol. Vis. 2014;20:307–324.
    1. Yang Z., Wang H., Jiang Y., Hartnett M.E. VEGFA activates erythropoietin receptor and enhances VEGFR2-mediated pathological angiogenesis. Am. J. Pathol. 2014;184:1230–1239. doi: 10.1016/j.ajpath.2013.12.023.
    1. Cavallaro G., Filippi L., Bagnoli P., La Marca G., Cristofori G., Raffaeli G., Padrini L., Araimo G., Fumagalli M., Groppo M., et al. The pathophysiology of retinopathy of prematurity: An update of previous and recent knowledge. Acta Ophthalmol. 2014;92:2–20. doi: 10.1111/aos.12049.
    1. Li Y., Lu Z., Keogh C.L., Yu S.P., Wei L. Erythropoietin-induced neurovascular protection, angiogenesis, and cerebral blood flow restoration after focal ischemia in mice. J. Cereb. Blood Flow Metab. 2006;27:1043–1054. doi: 10.1038/sj.jcbfm.9600417.
    1. Li Y., Lu Z.Y., Ogle M., Wei L. Erythropoietin prevents blood brain barrier damage induced by focal cerebral ischemia in mice. Neurochem. Res. 2007;32:2132–2141. doi: 10.1007/s11064-007-9387-9.
    1. Yan F., Zhang M., Meng Y., Li H., Yu L., Fu X., Tang Y., Jiang C. Erythropoietin improves hypoxic-ischemic encephalopathy in neonatal rats after short-term anoxia by enhancing angiogenesis. Brain Res. 2016;1651:104–113. doi: 10.1016/j.brainres.2016.09.024.
    1. Xiong Y., Zhang Y., Mahmood A., Meng Y., Qu C., Chopp M. Erythropoietin mediates neurobehavioral recovery and neurovascular remodeling following traumatic brain injury in rats by increasing expression of vascular endothelial growth factor. Transl. Stroke Res. 2011;2:619–632. doi: 10.1007/s12975-011-0120-2.
    1. Wang L., Chopp M., Teng H., Bolz M., Francisco M.A., Aluigi D.M., Wang X.L., Zhang R.L., Chrsitensen S., Sager T.N., et al. Tumor necrosis factor α primes cerebral endothelial cells for erythropoietin-induced angiogenesis. J. Cereb. Blood Flow Metab. 2011;31:640–647. doi: 10.1038/jcbfm.2010.138.
    1. Miyake M., Goodison S., Lawton A., Zhang G., Gomes-Giacoia E., Rosser C.J. Erythropoietin is a JAK2 and ERK1/2 effector that can promote renal tumor cell proliferation under hypoxic conditions. J. Hematol. Oncol. 2013;6:65. doi: 10.1186/1756-8722-6-65.
    1. El Hasnaoui-Saadani R., Pichon A., Marchant D., Olivier P., Launay T., Quidu P., Beaudry M., Duvallet A., Richalet J.P., Favret F. Cerebral adaptations to chronic anemia in a model of erythropoietin-deficient mice exposed to hypoxia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009;296:R801–R811. doi: 10.1152/ajpregu.00119.2008.
    1. Pichon A., Jeton F., El Hasnaoui-Saadani R., Hagstrom L., Launay T., Beaudry M., Marchant D., Quidu P., Macarlupu J.L., Favret F., et al. Erythropoietin and the use of a transgenic model of erythropoietin-deficient mice. Hypoxia. 2016;4:29–39.
    1. Lee S.T., Chu K., Park J.E., Jung K.H., Jeon D., Lim J.Y., Lee S.K., Kim M., Roh J.K. Erythropoietin improves memory function with reducing endothelial dysfunction and amyloid-β burden in Alzheimer’s disease models. J. Neurochem. 2012;120:115–124. doi: 10.1111/j.1471-4159.2011.07534.x.
    1. Rangarajan V., Juul S.E. Erythropoietin: Emerging role of erythropoietin in neonatal neuroprotection. Pediatr. Neurol. 2014;51:481–488. doi: 10.1016/j.pediatrneurol.2014.06.008.
    1. Yasuda Y., Fujita Y., Musha T., Tanaka H., Shiokawa S., Nakamatsu K., Mori S., Matsuo T., Nakamura Y. Expression of erythropoietin in human female reproductive organs. Ital. J. Anat. Embryol. 2001;106:215–222.
    1. Yasuda Y., Fujita Y., Masuda S., Musha T., Ueda K., Tanaka H., Fujita H., Matsuo T., Nagao M., Sasaki R., et al. Erythropoietin is involved in growth and angiogenesis in malignant tumours of female reproductive organs. Carcinogenesis. 2002;23:1797–1805. doi: 10.1093/carcin/23.11.1797.
    1. Hardee M.E., Cao Y., Fu P., Jiang X., Zhao Y., Rabbani Z.N., Vujaskovic Z., Dewhirst M.W., Arcasoy M.O. Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression. PLoS ONE. 2007;2:e549. doi: 10.1371/journal.pone.0000549.
    1. Yasuda Y., Fujita Y., Matsuo T., Koinuma S., Hara S., Tazaki A., Onozaki M., Hashimoto M., Musha T., Ogawa K., et al. Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis. 2003;24:1021–1029. doi: 10.1093/carcin/bgg060.
    1. Nakamatsu K., Nishimura Y., Suzuki M., Kanamori S., Maenishi O., Yasuda Y. Erythropoietin/erythropoietin-receptor system as an angiogenic factor in chemically induced murine hepatic tumors. Int. J. Clin. Oncol. 2004;9:184–188. doi: 10.1007/s10147-004-0399-z.
    1. Okazaki T., Ebihara S., Asada M., Yamanda S., Niu K., Arai H. Erythropoietin promotes the growth of tumors lacking its receptor and decreases survival of tumor-bearing mice by enhancing angiogenesis. Neoplasia. 2008;10:932–939. doi: 10.1593/neo.08140.
    1. Rupertus K., Senger S., Menger M.D., Schilling M.K., Kollmar O. Darbepoetin-α promotes neovascularization and cell proliferation in established colorectal liver metastases. J. Surg. Res. 2012;176:517–523. doi: 10.1016/j.jss.2011.09.062.
    1. Nico B., Annese T., Guidolin D., Finato N., Crivellato E., Ribatti D. EPO is involved in angiogenesis in human glioma. J. Neurooncol. 2011;102:51–58. doi: 10.1007/s11060-010-0294-6.
    1. Pascual M., Bohle B., Alonso S., Mayol X., Salvans S., Grande L., Pera M. Preoperative administration of erythropoietin stimulates tumor recurrence after surgical excision of colon cancer in mice by a vascular endothelial growth factor-independent mechanism. J. Surg. Res. 2013;183:270–277. doi: 10.1016/j.jss.2012.12.041.
    1. Ribatti D., Marzullo A., Gentile A., Longo V., Nico B., Vacca A., Dammacco F. Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinoma. Histopathology. 2007;50:591–596. doi: 10.1111/j.1365-2559.2007.02654.x.
    1. Ribatti D., Poliani P.L., Longo V., Mangieri D., Nico B., Vacca A. Erythropoietin/erythropoietin receptor system is involved in angiogenesis in human neuroblastoma. Histopathology. 2007;50:636–641. doi: 10.1111/j.1365-2559.2007.02653.x.
    1. Ribatti D. Erythropoietin and tumor angiogenesis. Stem Cells Dev. 2010;19:1–4. doi: 10.1089/scd.2009.0402.
    1. Ribatti D., Nico B., Perra M.T., Longo V., Maxia C., Annese T., Piras F., Murtas D., Sirigu P. Erythropoietin is involved in angiogenesis in human primary melanoma. Int. J. Exp. Pathol. 2010;91:495–499. doi: 10.1111/j.1365-2613.2010.00731.x.
    1. Wang L., Li H.G., Xia Z.S., Wen J.M., Lv J. Prognostic significance of erythropoietin and erythropoietin receptor in gastric adenocarcinoma. World J. Gastroenterol. 2011;17:3933–3940. doi: 10.3748/wjg.v17.i34.3933.
    1. Han Z.G., Yu T.T., Shan L. Expression of erythropoietin and erythropoietin receptor in non-small cell lung cancer and its correlation with microvessel density. Zhonghua Zhong Liu Za Zhi. 2012;34:605–608.
    1. Diensthuber M., Potinius M., Rodt T., Stan A.C., Welkoborsky H.J., Samii M., Schreyogg J., Lenarz T., Stover T. Expression of Bcl-2 is associated with microvessel density in olfactory neuroblastoma. J. Neurooncol. 2008;89:131–139. doi: 10.1007/s11060-008-9602-9.
    1. Kase S., Osaki M., Jin X.H., Ohgami K., Yoshida K., Saito W., Takahashi S., Nakanishi K., Ito H., Ohno S. Increased expression of erythropoietin receptor in human pterygial tissues. Int. J. Mol. Med. 2007;20:699–702.
    1. Ribatti D., Marzullo A., Nico B., Crivellato E., Ria R., Vacca A. Erythropoietin as an angiogenic factor in gastric carcinoma. Histopathology. 2003;42:246–250. doi: 10.1046/j.1365-2559.2003.01581.x.
    1. Tankiewicz-Kwedlo A., Hermanowicz J., Surazynski A., Rozkiewicz D., Pryczynicz A., Domaniewski T., Pawlak K., Kemona A., Pawlak D. Erythropoietin accelerates tumor growth through increase of erythropoietin receptor (EPOR) as well as by the stimulation of angiogenesis in DLD-1 and Ht-29 xenografts. Mol. Cell. Biochem. 2016;421:1–18. doi: 10.1007/s11010-016-2779-x.
    1. Qu Z., Jiang Y., Xu M., Lu M.Z., Zhou B., Ding Y. Correlation of adrenomedullin with the erythropoietin receptor and microvessel density in hepatocellular carcinoma. Arch. Med. Sci. 2015;11:978–981.
    1. Tovari J., Gilly R., Raso E., Paku S., Bereczky B., Varga N., Vago A., Timar J. Recombinant human erythropoietin α targets intratumoral blood vessels, improving chemotherapy in human xenograft models. Cancer Res. 2005;65:7186–7193. doi: 10.1158/0008-5472.CAN-04-2498.
    1. Lee A.S., Kim D.H., Lee J.E., Jung Y.J., Kang K.P., Lee S., Park S.K., Kwak J.Y., Lee S.Y., Lim S.T., et al. Erythropoietin induces lymph node lymphangiogenesis and lymph node tumor metastasis. Cancer Res. 2011;71:4506–4517. doi: 10.1158/0008-5472.CAN-10-3787.

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