Abstract
Human angiogenin is a 14-kDa secreted protein with angiogenic and ribonucleolytic activities. Angiogenin is associated with tumour development but is also present in normal biological fluids and tissues. To further address the physiological role of angiogenin, we studied its expression in situ and in vitro, using the human term placenta as a model of physiological angiogenesis. Angiogenin was immunodetected by light and transmission electron microscopy, and its cellular distribution was established by double immunolabelling with cell markers including von Willebrand factor, platelet/endothelial cell adhesion molecule-1 (PECAM-1), CD34, Tie-2, vascular endothelial cadherin (VE-cadherin), vascular endothelial growth factor receptor-2 (VEGF-R2), erythropoeitin receptor (Epo-R), alpha-smooth muscle actin, CD45, cytokeratin 7, and Ki-67. Angiogenin immunoreactivity was detected in villous and extravillous trophoblasts, the trophoblast basement membrane, the endothelial basal lamina, foetal blood vessels, foetal and maternal red blood cells, and amnionic cells. Its expression was confirmed by in situ hybridisation with a digoxygenin-labelled cDNA probe and reverse transcriptase-polymerase chain reaction amplification. Villous cytotrophoblasts, isolated and differentiated in vitro into a functional syncytiotrophoblast, expressed and secreted angiogenin. Given its known biological activities in vitro and its observed pattern of expression, these data suggest that, in human placenta, angiogenin has a role not only in angiogenesis but also in vascular and tissue homeostasis, maternal immune tolerance of the foetus, and host defences.
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References
Strydom DJ. The angiogenins. Cell Mol Life Sci 1998; 54: 811–24.
Badet J. Angiogenin. In Bikfalvi A (ed): Encyclopaedic Reference of Vascular Biology & Pathology. Berlin: Springer-Verlag 2000; 16–29.
Fett JW, Strydom DJ, Lobb RR et al. Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry 1985; 24: 5480–6.
Shapiro R, Strydom DJ, Olson KA, Vallee BL. Isolation of angiogenin from normal human plasma. Biochemistry 1987; 26: 5141–6.
Spong CY, Ghidini A, Sherer DM et al. Angiogenin: A marker for preterm delivery in midtrimester amniotic fluid. Am J Obstet Gynecol 1997; 176: 415–8.
Koga K, Osuga Y, Tsutsumi O et al. Evidence for the presence of angiogenin in human follicular fluid and the up-regulation of its production by human chorionic gonadotropin and hypoxia. J Clin Endocrinol Metab 2000; 85: 3352–5.
Weiner HL, Weiner LH, Swain JL. Tissue distribution and developmental expression of the messenger RNA encoding angiogenin. Science 1987; 237: 280–2.
Malamitsi-Puchner A, Sarandakou A, Giannaki G et al. Changes of angiogenin serum concentrations in the perinatal period. Pediatr Res 1997; 41: 909–11.
Futami J, Tsushima Y, Murato Y et al. Tissue-specific expression of pancreatic-type RNases and RNase inhibitor in humans. DNA Cell Biol 1997; 16: 413–9.
Riordan JF. Structure and function of angiogenin. In D'Alessio G, Riordan JF (eds): Ribonucleases: Structure and Functions. New York: Academic Press 1997; 445–89.
Hertig AT. Angiogenesis in the early human chorion and in the primary placenta of the macaque monkey. Contr Embryol Carnegie Inst 1935; 25: 37–81.
Charnock-Jones DS, Burton GJ. Placental vascular morphogenesis. Baillieres Best Pract Res Clin Obstet Gynaecol 2000; 14: 953–68.
Bernirscke K, Kaufmann P. Pathology of the Human Placenta, 4th edition. New York: Springer-Verlag 2000.
Cross JC, Werb Z, Fisher SJ. Implantation and the placenta: Key pieces of the development puzzle. Science 1994; 266: 1508–18.
Hatzi E, Badet J. Expression of receptors for human angiogenin in vascular smooth muscle cells. Eur J Biochem 1999; 260: 825–32.
Kliman HJ, Nestler JE, Sermasi E et al. Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology 1986; 118: 1567–82.
Alsat E, Haziza J, Evain-Brion D. Increase in epidermal growth factor receptor and its messenger ribonucleic acid levels with differentiation of human trophoblast cells in culture. J Cell Physiol 1993; 154: 122–8.
Westphal JR, Van't Hullenaar R, Peek R et al. Angiogenic balance in human melanoma: Expression of VEGF, bFGF, IL-8, PDGF and angiostatin in relation to vascular density of xenografts in vivo. Int J Cancer 2000; 86: 768–76.
Olson KA, Byers HR, Key ME, Fett JW. Inhibition of prostate carcinoma establishment and metastatic growth in mice by an antiangiogenin monoclonal antibody. Int J Cancer 2002; 98: 923–9.
Rajashekhar G, Loganath A, Roy AC, Wong YC. Expression and localization of angiogenin in placenta: Enhanced levels at term over first trimester villi. Mol Reprod Dev 2002; 62: 159–66.
Dye JF, Jablenska R, Donnelly JL et al. Phenotype of the endothelium in the human term placenta. Placenta 2001; 22: 32–43.
Nakamura Y, Ohta Y. Immunohistochemical study of human placental stromal cells. Hum Pathol 1990; 21: 936–40.
Moroianu J, Riordan JF. Identification of the nucleolar targeting signal of human angiogenin. Biochem Biophys Res Commun 1994; 203: 1765–72.
Lixin R, Efthymiadis A, Henderson B, Jans DA. Novel properties of the nucleolar targeting signal of human angiogenin. Biochem Biophys Res Commun 2001; 284: 185–93.
Hoffman LH, Wooding FB. Giant and binucleate trophoblast cells of mammals. J Exp Zool 1993; 266: 559–77.
Demir R, Kaufmann P, Castellucci M et al. Fetal vasculogenesis and angiogenesis in human placental villi. Acta Anat (Basel) 1989; 136: 190–203.
Mayhew TM. Fetoplacental angiogenesis during gestation is biphasic, longitudinal and occurs by proliferation and remodelling of vascular endothelial cells. Placenta 2002; 23: 742–50.
Moenner M, Gusse M, Hatzi E, Badet J. The widespread expression of angiogenin in different human cells suggests a biological function not only related to angiogenesis. Eur J Biochem 1994; 226: 483–90.
Badet J, Soncin F, Guitton J-D et al. Specific binding of angiogenin to calf pulmonary artery endothelial cells. Proc Natl Acad Sci USA 1989; 86: 8427–33.
Bicknell R, Vallee BL. Angiogenin stimulates endothelial cell prostacyclin secretion by activation of phospholipase A2. Proc Natl Acad Sci USA 1989; 86: 1573–7.
Moore F, Riordan JF. Angiogenin activates phospholipase C and elicits a rapid incorporation of fatty acid into cholesterol esters in vascular smooth muscle cells. Biochemistry 1990; 29: 228–33.
Hu G-F, Riordan JF, Vallee BL. Angiogenin promotes invasiveness of cultured endothelial cells by stimulation of cell-associated proteolytic activities. Proc Natl Acad Sci USA 1994; 91: 12096–100.
Chamoux M, Dehouck MP, Fruchart JC et al. Characterization of angiogenin receptors on bovine brain capillary endothelial cells. Biochem Biophys Res Commun 1991; 176: 833–9.
Hu G-F, Riordan JF, Vallee BL. A putative angiogenin receptor in angiogenin-responsive human endothelial cells. Proc Natl Acad Sci USA 1997; 94: 2204–9.
Xu Z, Monti DM, Hu G. Angiogenin activates human umbilical artery smooth muscle cells. Biochem Biophys Res Commun 2001; 285: 909–14.
Thyberg J. Differentiated properties and proliferation of arterial smooth muscle cells in culture. Int Rev Cytol 1996; 169: 183–265.
King TV, Vallee BL. Neovascularisation of the meniscus with angiogenin. An experimental study in rabbits. J Bone Joint Surg (Br) 1991; 73–B: 587–90.
Raines RT, Toscano MP, Nierengarten DM et al. Replacing a surface loop endows ribonuclease A with angiogenic activity. J Biol Chem 1995; 270: 17180–4.
Tordjman R, Delaire S, Plouet J et al. Erythroblasts are a source of angiogenic factors. Blood 2001; 97: 1968–74.
Soncin F, Strydom DJ, Shapiro R. Interaction of heparin with human angiogenin. J Biol Chem 1997; 272: 9818–24.
Taipale J, Keski-Oja J. Growth factors in the extracellular matrix. FASEB J 1997; 11: 51–9.
Aplin JD. Implantation, trophoblast differentiation and haemochorial placentation: Mechanistic evidence in vivo and in vitro. J Cell Sci 1991; 99: 681–92.
Soncin F. Angiogenin supports endothelial and fibroblast cell adhesion. Proc Natl Acad Sci USA 1992; 89: 2232–6.
Soncin F, Shapiro R, Fett JW. A cell-surface proteoglycan mediates human adenocarcinoma HT-29 cell adhesion to human angiogenin. J Biol Chem 1994; 269: 8999–9005.
Tschesche H, Kopp C, Horl WH, Hempelmann U. Inhibition of degranulation of polymorphonuclear leukocytes by angiogenin and its tryptic fragment. J Biol Chem 1994; 269: 30274–80.
Matousek J, Soucek J, Riha J et al. Immunosuppressive activity of angiogenin in comparison with bovine seminal ribonuclease and pancreatic ribonuclease. Comp Biochem Physiol 1995; 112B: 235–41.
Bowen JM, Chamley L, Keelan JA, Mitchell MD. Cytokines of the placenta and extra-placental membranes: Roles and regulation during human pregnancy and parturition. Placenta 2002; 23: 257–73.
Yoon BH, Oh SY, Romero R et al. An elevated amniotic fluid matrix metalloproteinase-8 level at the time of mid-trimester genetic amniocentesis is a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol 2001; 185: 1162–7.
Olson KA, Verselis SJ, Fett JW. Angiogenin is regulated in vivo as an acute phase protein. Biochem Biophys Res Commun 1998; 242: 480–3.
Verselis SJ, Olson KA, Fett JW. Regulation of angiogenin expression in human HepG2 hepatoma cells by mediators of the acute-phase response. Biochem Biophys Res Commun 1999; 259: 178–84.
Hooper LV, Stappenbeck TS, Hong CV, Gordon JI. Angiogenins: A new class of microbicidal proteins involved in innate immunity. Nat Immunol 2003; 4: 269–73.
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Pavlov, N., Hatzi, E., Bassaglia, Y. et al. Angiogenin Distribution in Human Term Placenta, and Expression by Cultured Trophoblastic Cells. Angiogenesis 6, 317–330 (2003). https://doi.org/10.1023/B:AGEN.0000029412.95244.81
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DOI: https://doi.org/10.1023/B:AGEN.0000029412.95244.81