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Pathology of the Human Placenta pp 101–144Cite as

Architecture of Normal Villous Trees

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Abstract

Placental villi can be classified into subtypes that differ principally in their caliber, stromal, and vessel architecture, position within the villous tree, and function (Fig. 7.1). Several classification systems have been used in the past, but the one most commonly employed today was introduced by Kaufmann and colleagues (1979). This recognizes the following villous types (Fig.7.2).

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References

  • Ahmed A, Perkins J (2000) Angiogenesis and intrauterine growth restriction. Baillieres Best Pract Res Clin Obstet Gynaecol 14:981–988

    Article  PubMed  CAS  Google Scholar 

  • Ahmed A, Li XF, Dunk C, Whittle MJ, Rushton DI, Rollason T (1995) Colocalisation of vascular endothelial growth factor and its flt-1 receptor in human placenta. Growth Factors 12:235–243

    Article  PubMed  CAS  Google Scholar 

  • Ahmed A, Dunk C, Ahmad S, Khaliq A (2000) Regulation of placental vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) and soluble Flt-1 by oxygen – a review. Placenta 21(Suppl A):S16–S24

    Article  PubMed  Google Scholar 

  • Alfaidy N, Gupta S, DeMarco C, Caniggia I, Challis JRG (2002) Oxygen regulation of placental 11β-hydroxysteroid dehydrogenase 2: physiological and pathological implications. J Clin Endocrinol Metab 87:4797–4805

    Article  PubMed  CAS  Google Scholar 

  • Ali KZM (1997) Stereological study of the effect of altitude on the trophoblast cell populations of human term placental villi. Placenta 18:447–450

    Article  PubMed  CAS  Google Scholar 

  • Ali KZM, Burton GJ, Morad N, Ali ME (1996) Does hypercapillarization influence the branching pattern of terminal villi in the human placenta at high altitude? Placenta 17:677–682

    Article  PubMed  CAS  Google Scholar 

  • Alsat E, Wyplosz P, Malassiné A (1996) Hypoxia impairs cell fusion and differentiation process in human cytotrophoblast cells, in vitro. J Cell Physiol 168:346–353

    Article  PubMed  CAS  Google Scholar 

  • Alvarez H, Benedetti WL, Morel RL, Scavarelli M (1970) Trophoblast development gradient and its relationship to placental hemodynamics. Am J Obstet Gynecol 106:416–420

    PubMed  CAS  Google Scholar 

  • Anson-Cartwright L, Dawson K, Holmyard D, Fisher SJ, Lazzarini RA, Cross JC (2000) The glial cells missing-1 protein is essential for branching morphogenesis in the chorioallantoic placenta. Nat Genet 25:311–314

    Article  PubMed  CAS  Google Scholar 

  • Anteby EY, Natanson-Yaron S, Greenfield C, Goldman-Wohl D, Haimov-Kochman R, Holzer H, Yagel S (2005) Human placental Hofbauer cells express sprouty proteins: a possible modulating mechanism of villous branching. Placenta 26:476–483

    Article  PubMed  CAS  Google Scholar 

  • Arnholdt H, Meisel F, Fandrey K, Lohrs U (1991) Proliferation of villous trophoblast of the human placenta in normal and abnormal pregnancies. Virchows Arch B Cell Pathol Incl Mol Pathol 60:365–372

    Article  PubMed  CAS  Google Scholar 

  • Asan E, Kaymaz FF, Cakar AN, Dagdeviren A, Beksac MS (1999) Vasculogenesis in early human placental villi: an ultrastructural study. Ann Anat 181:549–554

    Article  PubMed  CAS  Google Scholar 

  • Bacon BJ, Gilbert RD, Kaufman P, Dwight Smith A, Trevino FT, Longo LD (1984) Placental anatomy and diffusing capacity in guinea pigs following long-term maternal hypoxia. Placenta 5:475–488

    Article  PubMed  CAS  Google Scholar 

  • Baczyk D, Satkunaratnam A, Nait-Oumesma RB, Huppertz B, Cross JC, Kingdom JC (2004) Complex patterns of GCM1 mRNA and protein in villous and extravillous trophoblast cells of the human placenta. Placenta 25:553–559

    Article  PubMed  CAS  Google Scholar 

  • Bainbridge SA, Belkacemi L, Dickinson M, Graham CH, Smith GN (2006) Carbon monoxide inhibits hypoxia/reoxygenation-induced apoptosis and secondary necrosis in syncytiotrophoblast. Am J Pathol 169:774–783

    Article  PubMed  CAS  Google Scholar 

  • Baker PN, Krasnow J, Roberts JM, Yeo KT (1995) Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol 86:815–821

    Article  PubMed  CAS  Google Scholar 

  • Banks RE, Forbes MA, Searles J, Pappin D, Canas B, Rahman D, Kaufmann S, Walters CE, Jackson A, Eves P, Linton G, Keen J, Walker JJ, Selby PJ (1998) Evidence for the existence of a novel pregnancy-associated soluble variant of the vascular endothelial growth factor receptor, Flt-1. Mol Hum Reprod 4:377–386

    Article  PubMed  CAS  Google Scholar 

  • Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C, Li JC, Liang Y, McCormack M, Montgomery HE, Pan H, Robbins PA, Shianna KV, Tam SC, Tsering N, Veeramah KR, Wang W, Wangdui P, Weale ME, Xu Y, Xu Z, Yang L, Zaman MJ, Zeng C, Zhang L, Zhang X, Zhaxi P, Zheng YT (2010) Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci USA 107: 11459–11464

    Article  PubMed  CAS  Google Scholar 

  • Beischer NA, Sivasamboo R, Vohra S, Silpisornkosal S, Reid S (1970) Placental hypertrophy in severe pregnancy anaemia. J Obstet Gynaecol Br Commonw 77:398–409

    Article  PubMed  CAS  Google Scholar 

  • Benyo DF, Miles TM, Conrad KP (1997) Hypoxia stimulates cytokine production by villous explants from the human placenta. J Clin Endocrinol Metab 82:1582–1588

    Article  PubMed  CAS  Google Scholar 

  • Biron-Shental T, Schaiff WT, Rimon E, Shim TL, Nelson DM, Sadovsky Y (2008) Hypoxia enhances the expression of follistatin-like 3 in term human trophoblasts. Placenta 29:51–57

    Article  PubMed  CAS  Google Scholar 

  • Boe F (1969) Studies on the human placenta. 3. Vascularization of the young foetal placenta. B. Vascularization of the translucent villus and the syncytial band, with special reference to the cell islands and the basal plate. Acta Obstet Gynecol Scand 48:167–186

    Article  PubMed  CAS  Google Scholar 

  • Bouw GM, Stolte LAM, Baak JPA, Oort J (1976) Quantitative morphology of the placenta. I. Standardization of sampling. Eur J Obstet Gynecol Reprod Biol 6:325–331

    Article  Google Scholar 

  • Boyd JD, Hamilton WJ (1970) The human placenta. Heffer and Sons, Cambridge

    Google Scholar 

  • Brosens I, Robertson WB, Dixon HG (1972) The role of spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu 1:177–191

    PubMed  CAS  Google Scholar 

  • Burchell C (1969) Arterial blood flow in the human intervillous space. Am J Obstet Gynecol 98:303–311

    Google Scholar 

  • Burton GJ (1987) The fine structure of the human placenta as revealed by scanning electron microscopy. Scanning Microsc 1:1811–1828

    PubMed  CAS  Google Scholar 

  • Burton GJ (1997) On ‘oxygen and placental villous development: origins of fetal hypoxia’. Placenta 18:625–626

    Article  Google Scholar 

  • Burton GJ (2009) Oxygen, the Janus gas; its effects on human placental development and function. J Anat 215:27–35

    Article  PubMed  CAS  Google Scholar 

  • Burton GJ, Jauniaux E (1995) Sonographic, stereological and Doppler flow velocimetric assessments of placental maturity. Br J Obstet Gynaecol 102:818–825

    Article  PubMed  CAS  Google Scholar 

  • Burton GJ, Tham SW (1992) The formation of vasculo-syncytial membranes in the human placenta. J Dev Physiol 18:43–47

    PubMed  CAS  Google Scholar 

  • Burton GJ, Ingram SC, Palmer ME (1987) The influence of the mode of fixation on morphometrical data derived from terminal villi in the human placenta at term: a comparison of immersion and perfusion fixation. Placenta 8:37–51

    Article  PubMed  CAS  Google Scholar 

  • Burton GJ, Thurley KW, Skepper JN (1991) A technique for correlative scanning and transmission electron microscopy of individual human placental villi: an example demonstrating syncytial sprouts in early gestation. Scanning Microsc 5:451–458

    PubMed  CAS  Google Scholar 

  • Burton GJ, Reshetnikova OS, Milovanov AP, Teleshova OV (1996) Stereological evaluation of vascular adaptations of human placental villi to differing forms of hypoxic stress. Placenta 17:49–55

    Article  PubMed  CAS  Google Scholar 

  • Burton GJ, Watson AL, Hempstock J, Skepper JN, Jauniaux E (2002) Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J Clin Endocrinol Metab 87:2954–2959

    Article  PubMed  CAS  Google Scholar 

  • Burton GJ, Jauniaux E, Charnock-Jones DS (2007) Human early placental development: potential roles of the endometrial glands. Placenta 28(Suppl A):S64–S69

    Article  PubMed  CAS  Google Scholar 

  • Burton GJ, Charnock-Jones DS, Jauniaux E (2009a) Regulation of ­vascular growth and function in human placenta. Reproduction 138:895–902

    Article  PubMed  CAS  Google Scholar 

  • Burton GJ, Yung HW, Cindrova-Davies T, Charnock-Jones DS (2009b) Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta 30(Suppl A):S43–S48

    Article  PubMed  CAS  Google Scholar 

  • Burton GJ, Woods AW, Jauniaux E, Kingdom JC (2009c) Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 30:473–482

    Article  PubMed  CAS  Google Scholar 

  • Caniggia I, Winter JL (2002) Adriana and Luisa castellucci award lecture 2001 hypoxia inducible factor-1: oxygen regulation of trophoblast differentiation in normal and Pre-eclamptic pregnancies-a review. Placenta 23(Suppl A):S47–S57

    Article  PubMed  Google Scholar 

  • Caniggia I, Winter J, Lye SJ, Post M (2000a) Oxygen and placental development during the first trimester: implications for the pathophysiology of preeclampsia. Placenta 21(Suppl A):S25–S30

    Article  PubMed  Google Scholar 

  • Caniggia I, Mostachfi H, Winter J, Gassmann M, Lye SJ, Kuliszewski M, Post M (2000b) Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3). J Clin Invest 105:577–587

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P, Mackman N, Moons L, Luther T, Gressens P, Van Vlaenderen I, Demunck H, Kasper M, Breier G, Evrard P, Muller M, Risau W, Edgington T, Collen D (1996) Role of tissue factor in embryonic blood vessel development. Nature 383:73–75

    Article  PubMed  CAS  Google Scholar 

  • Carter AM (2000) Placental oxygen consumption. Part I: in vivo studies-a review. Placenta 21(Suppl A):S31–S37

    Article  PubMed  Google Scholar 

  • Castellucci M, Kaufmann P (1982) A three-dimensional study of the normal human placental villous core: II. Stromal architecture. Placenta 3:269–286

    Article  PubMed  CAS  Google Scholar 

  • Castellucci M, Schweikhart G, Kaufmann P, Zaccheo D (1984) The stromal architecture of the immature intermediate villus of the human placenta. Functional and clinical implications. Gynecol Obstet Invest 18:95–99

    Article  PubMed  CAS  Google Scholar 

  • Castellucci M, Kosanke G, Verdenelli F, Huppertz B, Kaufmann P (2000) Villous sprouting: fundamental mechanisms of human placental development. Hum Reprod Update 6:485–494

    Article  PubMed  CAS  Google Scholar 

  • Challier JC, Galtier M, Kacemi A, Guillaumin D (1999) Pericytes of term human foeto-placental microvessels: ultrastructure and visualization. Cell Mol Biol (Noisy-le-Grand) 45:89–100

    CAS  Google Scholar 

  • Chang M, Mukherjea D, Gobble RM, Groesch KA, Torry RJ, Torry DS (2008) Glial cell missing 1 regulates placental growth factor (PGF) gene transcription in human trophoblast. Biol Reprod 78:841–851

    Article  PubMed  CAS  Google Scholar 

  • Chappell LC, Seed PT, Briley A, Kelly FJ, Hunt BJ, Charnock-Jones DS, Mallet AI, Poston L (2002) A longitudinal study of biochemical variables in women at risk of preeclampsia. Am J Obstet Gynecol 187:127–136

    Article  PubMed  Google Scholar 

  • Charnock-Jones D (2002) Soluble flt and the angiopoietins in the development and regulation of placental vasculature. J Anat 200:607–615

    Article  PubMed  CAS  Google Scholar 

  • Charnock-Jones DS, Burton GJ (2000) Placental vascular morphogenesis. Baillieres Best Pract Res Clin Obstet Gynaecol 14:953–968

    Article  PubMed  CAS  Google Scholar 

  • Charnock-Jones DS, Kaufmann P, Mayhew TM (2004) Aspects of human fetoplacental vasculogenesis and angiogenesis. I. Molecular recognition. Placenta 25:103–113

    Article  PubMed  CAS  Google Scholar 

  • Chen C-P, Aplin JD (2003) Placental extracellular matrix: gene expression, deposition by placental fibroblasts and the effect of oxygen. Placenta 24:316–325

    Article  PubMed  CAS  Google Scholar 

  • Chen K, Thomas SR, Keaney JF (2003) Beyond LDL oxidation: ROS in vascular signal transduction. Free Radic Biol Med 35:117–132

    Article  PubMed  CAS  Google Scholar 

  • Chernyavsky IL, Jensen OE, Leach L (2010) A mathematical model of intervillous blood flow in the human placentone. Placenta 31:44–52

    Article  PubMed  CAS  Google Scholar 

  • Chiang MH, Liang FY, Chen CP, Chang CW, Cheong ML, Wang LJ, Liang CY, Lin FY, Chou CC, Chen H (2009) Mechanism of hypoxia-induced GCM1 degradation: implications for the pathogenesis of preeclampsia. J Biol Chem 284:17411–17419

    Article  PubMed  CAS  Google Scholar 

  • Cindrova-Davies T (2009) From placental oxidative stress to maternal endothelial dysfunction. Placenta 30(Suppl A):S55–S65

    Article  PubMed  CAS  Google Scholar 

  • Cindrova-Davies T, Yung HW, Johns J, Spasic-Boskovic O, Korolchuk S, Jauniaux E, Burton GJ, Charnock-Jones DS (2007a) Oxidative stress, gene expression, and protein changes induced in the human placenta during labor. Am J Pathol 171:1168–1179

    Article  PubMed  CAS  Google Scholar 

  • Cindrova-Davies T, Spasic-Boskovic O, Jauniaux E, Charnock-Jones DS, Burton GJ (2007b) Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins. Am J Pathol 170:1511–1520

    Article  PubMed  CAS  Google Scholar 

  • Cindrova-Davies T, Sanders DA, Burton GJ, Charnock-Jones DS (2011) Soluble FLT1 sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGF receptor-mediated signalling. Cardiovasc Res 89:671–679

    Article  PubMed  CAS  Google Scholar 

  • Clark DE, Smith SK, Sharkey AM, Charnock-Jones DS (1996a) Localization of VEGF and expression of its receptors flt and KDR in human placenta throughout pregnancy. Hum Reprod 11:1090–1098

    Article  PubMed  CAS  Google Scholar 

  • Clark DE, Smith SK, Sharkey AM, Sowter HM, Charnock-Jones DS (1996b) Hepatocyte growth factor scatter factor and its receptor c-met: localization and expression in the human placenta throughout pregnancy. J Endocrinol 151:459–467

    Article  PubMed  CAS  Google Scholar 

  • Clark DE, Salvig JD, Smith SK, Charnock-Jones DS (1998a) Hepatocyte growth factor levels during normal and intra-uterine growth-restricted pregnancies. Placenta 19:671–673

    Article  PubMed  CAS  Google Scholar 

  • Clark DE, Smith SK, He Y, Day KA, Licence DR, Corps AC, Lammoglia R, Charnock-Jones DS (1998b) A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol Reprod 59:1540–1548

    Article  PubMed  CAS  Google Scholar 

  • Clark DE, Smith SK, Licence D, Evans AL, Charnock-Jones DS (1998c) Comparison of expression patterns for placenta growth factor, vascular endothelial growth factor (VEGF), VEGF-B and VEGF-C in the human placenta throughout gestation. J Endocrinol 159:459–467

    Article  PubMed  CAS  Google Scholar 

  • Conrad PW, Conforti L, Kobayashi S, Beitner-Johnson D, Rust RT, Yuan Y, Kim HW, Kim RH, Seta K, Millhorn DE (2001) The molecular basis of O2-sensing and hypoxia tolerance in pheochromocytoma cells. Comp Biochem Physiol B Biochem Mol Biol 128:187–204

    Article  PubMed  CAS  Google Scholar 

  • Critchley GR, Burton GJ (1987) Intralobular variations in barrier thickness in the mature human placenta. Placenta 8:185–194

    Article  PubMed  CAS  Google Scholar 

  • Cross JC, Simmons DG, Watson ED (2003) Chorioallantoic morphogenesis and formation of the placental villous tree. Ann N Y Acad Sci 995:84–93

    Article  PubMed  CAS  Google Scholar 

  • Cross JC, Nakano H, Natale DR, Simmons DG, Watson ED (2006) Branching morphogenesis during development of placental villi. Differentiation 74:393–401

    Article  PubMed  CAS  Google Scholar 

  • Cullinan SB, Diehl JA (2006) Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38:317–332

    Article  PubMed  CAS  Google Scholar 

  • Dantzer V, Leiser R, Kaufmann P, Luckhardt M (1988) Comparative morphological aspects of placental vascularisation. Trophoblast Res 3:235–260

    Google Scholar 

  • Dechend R, Viedt C, Muller DN, Ugele B, Brandes RP, Wallukat G, Park J-K, Janke J, Barta P, Theuer J, Fiebler A, Homuth V, Dietz R, Haller H, Kreuzer J, Luft FC (2003) AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase. Circulation 107:1632–1639

    Article  PubMed  CAS  Google Scholar 

  • Demir R, Kaufmann P, Castellucci M, Erbengi T, Kotowski A (1989) Fetal vasculogenesis and angiogenesis in human placental villi. Acta Anat 136:190–203

    Article  PubMed  CAS  Google Scholar 

  • Demir R, Kosanke G, Kohnen G, Kertschanska S, Kaufmann P (1997) Classification of human placental stem villi: review of structural and functional aspects. Microsc Res Tech 38:29–41

    Article  PubMed  CAS  Google Scholar 

  • Demir R, Kayisli UA, Seval Y, Celik-Ozenci C, Korgun ET, Demir-Weusten AY, Huppertz B (2004) Sequential expression of VEGF and its receptors in human placental villi during very early pregnancy: differences between placental vasculogenesis and angiogenesis. Placenta 25:560–572

    Article  PubMed  CAS  Google Scholar 

  • Demir R, Kayisli UA, Cayli S, Huppertz B (2006) Sequential steps ­during vasculogenesis and angiogenesis in the very early human placenta. Placenta 27:535–539

    Article  PubMed  CAS  Google Scholar 

  • Demir R, Seval Y, Huppertz B (2007) Vasculogenesis and angiogenesis in the early human placenta. Acta Histochem 109:257–265

    Article  PubMed  CAS  Google Scholar 

  • Dempsey EW (1972) The development of capillaries in the villi of early human placentas. Am J Anat 134:221–238

    Article  PubMed  CAS  Google Scholar 

  • Di Blasio AM, Carniti C, Vigano P, Florio P, Petraglia F, Vignali M (1997) Basic fibroblast growth factor messenger ribonucleic acid levels in human placentas from normal and pathological pregnancies. Mol Hum Reprod 3:1119–1123

    Article  PubMed  Google Scholar 

  • Downs KM, Gifford S, Blahnik M, Gardner RL (1998) Vascularization in the murine allantois occurs by vasculogenesis without accompanying erythropoiesis. Development 125:4507–4520

    PubMed  CAS  Google Scholar 

  • Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95

    PubMed  CAS  Google Scholar 

  • Dunk C, Shams M, Nijjar S, Rhaman M, Qiu Y, Bussolati B, Ahmed A (2000) Angiopoietin-1 and angiopoietin-2 activate trophoblast Tie-2 to promote growth and migration during placental development. Am J Pathol 156:2185–2199

    Article  PubMed  CAS  Google Scholar 

  • Dunwoodie SL (2009) The role of hypoxia in development of the mammalian embryo. Dev Cell 17:755–773

    Article  PubMed  CAS  Google Scholar 

  • Espinoza J, Sebire NJ, McAuliffe F, Krampl E, Nicolaides KH (2001) Placental villus morphology in relation to maternal hypoxia at high altitude. Placenta 22:606–608

    Article  PubMed  CAS  Google Scholar 

  • Esterman A, Finlay TH, Dancis J (1996) The effect of hypoxia on term trophoblast: hormone synthesis and release. Placenta 17:217–222

    Article  PubMed  CAS  Google Scholar 

  • Evans PW, Wheeler T, Anthony FW, Osmond C (1998) A longitudinal study of maternal serum vascular endothelial growth factor in early pregnancy. Hum Reprod 13:1057–1062

    Article  PubMed  CAS  Google Scholar 

  • Fahling M (2009) Cellular oxygen sensing, signalling and how to ­survive translational arrest in hypoxia. Acta Physiol (Oxf) 195:205–230

    Article  CAS  Google Scholar 

  • Farley AE, Graham CH, Smith GN (2004) Contractile properties of human placental anchoring villi. Am J Physiol Regul Integr Comp Physiol 287:R680–R685

    Article  PubMed  CAS  Google Scholar 

  • Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL (1999) Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 59:3915–3918

    PubMed  CAS  Google Scholar 

  • Feneley MR, Burton GJ (1991) Villous composition and membrane thickness in the human placenta at term: a stereological study using unbiased estimators and optimal fixation techniques. Placenta 12:131–142

    Article  PubMed  CAS  Google Scholar 

  • Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442

    Article  PubMed  CAS  Google Scholar 

  • Ferriani RA, Ahmed A, Sharkey A, Smith SK (1994) Colocalization of acidic and basic fibroblast growth factor (FGF) in human placenta and the cellular effects of bFGF in trophoblast cell line JEG-3. Growth Factors 10:259–268

    Article  PubMed  CAS  Google Scholar 

  • Fong GH, Zhang L, Bryce DM, Peng J (1999) Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development 126:3015–3025

    PubMed  CAS  Google Scholar 

  • Fox H (1964) The villous cytotrophoblast as an index of placental ischaemia. J Obstet Gynaecol Br Commonw 71:885–893

    Article  PubMed  CAS  Google Scholar 

  • Fox H (1967) The incidence and significance of vasculo-syncytial membranes in the human placenta. J Obstet Gynaecol Br Commonw 47:28–33

    Article  Google Scholar 

  • Fox H (1970) Effect of hypoxia on trophoblast in organ culture. A morphologic and autoradiographic study. Am J Obstet Gynecol 107:1058–1064

    PubMed  CAS  Google Scholar 

  • Fox H (1997) Pathology of the placenta. WB Saunders, London

    Google Scholar 

  • Freese UE (1968) The uteroplacental vascular relationship in the human. Am J Obstet Gynecol 101:8–16

    PubMed  CAS  Google Scholar 

  • Genbacev O, Joslin R, Damsky CH, Polliotti BM, Fisher SJ (1996) Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J Clin Invest 97:540–550

    Article  PubMed  CAS  Google Scholar 

  • Genbacev O, Zhou Y, Ludlow JW, Fisher SJ (1997) Regulation of human placental development by oxygen tension. Science 277:1669–1672

    Article  PubMed  CAS  Google Scholar 

  • Ghosh R, Lipson KL, Sargent KE, Mercurio AM, Hunt JS, Ron D, Urano F (2010) Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS One 5:e9575

    Article  PubMed  CAS  Google Scholar 

  • Gorski DH, Walsh K (2003) Control of vascular cell differentiation by homeobox transcription factors. Trends Cardiovasc Med 13:213–220

    Article  PubMed  CAS  Google Scholar 

  • Graham CH, Postovit LM, Park H, Canning MT, Fitzpatrick TE (2000) Adriana and Luisa Castellucci award lecture 1999: role of oxygen in the regulation of trophoblast gene expression and invasion. Placenta 21:443–450

    Article  PubMed  CAS  Google Scholar 

  • Gundersen HJG, Jensen EB (1985) Stereological estimation of the ­volume weighted mean volume of arbitrary particles observed on random sections. J Microsc 138:127–142

    Article  PubMed  CAS  Google Scholar 

  • Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine. Oxford Science, Oxford

    Google Scholar 

  • Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633

    Article  PubMed  CAS  Google Scholar 

  • He Y, Smith SK, Day KA, Clark DE, Licence DR, Charnock-Jones DS (1999) Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for the regulation of VEGF activity. Mol Endocrinol 13:537–545

    Article  PubMed  CAS  Google Scholar 

  • Helske S, Vuorela P, Carpen O, Hornig C, Weich H, Halmesmaki E (2001) Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentas from normal and complicated pregnancies. Mol Hum Reprod 7:205–210

    Article  PubMed  CAS  Google Scholar 

  • Hemberger M, Udayashankar R, Tesar P, Moore H, Burton GJ (2010) ELF5-enforced transcriptional networks define an epigentically regulated trophoblast stem cell compartment in the human placenta. Hum Mol Genet 19:2456–2467

    Article  PubMed  CAS  Google Scholar 

  • Hempstock J, Bao Y-P, Bar-Issac M, Segaren N, Watson AL, Charnock-Jones DS, Jauniaux E, Burton GJ (2003a) Intralobular differences in antioxidant enzyme expression and activity reflect oxygen gradients within the human placenta. Placenta 24:517–523

    Article  PubMed  CAS  Google Scholar 

  • Hempstock J, Jauniaux E, Greenwold N, Burton GJ (2003b) The contribution of placental oxidative stress to early pregnancy failure. Hum Pathol 34:1265–1275

    Article  PubMed  CAS  Google Scholar 

  • Hornig C, Barleon B, Ahmad S, Vuorela P, Ahmed A, Weich HA (2000) Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids. Lab Invest 80:443–454

    Article  PubMed  CAS  Google Scholar 

  • Hung TH, Burton GJ (2006) Hypoxia and reoxygenation: a possible mechanism for placental oxidative stress in preeclampsia. Taiwan J Obstet Gynecol 45:189–200

    Article  PubMed  Google Scholar 

  • Hung TH, Skepper JN, Burton GJ (2001) In vitro ischemia-reperfusion injury in term human placenta as a model for oxidative stress in pathological pregnancies. Am J Pathol 159:1031–1043

    Article  PubMed  CAS  Google Scholar 

  • Hung T-H, Skepper JN, Charnock-Jones DS, Burton GJ (2002) Hypoxia/reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ Res 90:1274–1281

    Article  PubMed  CAS  Google Scholar 

  • Hung T-H, Charnock-Jones DS, Skepper JN, Burton GJ (2004) Secretion of tumour necrosis factor-a from human placental tissues induced by hypoxia-reoxygenation causes endothelial cell activation in vitro: a potential mediator of the inflammatory response in preeclampsia. Am J Pathol 164:1049–1061

    Article  PubMed  CAS  Google Scholar 

  • Hung TH, Chen SF, Hsieh TT, Lo LM, Li MJ, Yeh YL (2011) The associations between labor and delivery mode and maternal and placental oxidative stress. Reprod Toxicol 31(2):144–150

    Article  PubMed  CAS  Google Scholar 

  • Huppertz B, Kingdom J, Caniggia I, Desoye G, Black S, Korr H, Kaufmann P (2003) Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation. Placenta 24:181–190

    Article  PubMed  CAS  Google Scholar 

  • Ietta F, Wu Y, Winter J, Xu J, Wang J, Post M, Caniggia I (2006) Dynamic HIF1A regulation during human placental development. Biol Reprod 75:112–121

    Article  PubMed  CAS  Google Scholar 

  • Ietta F, Wu Y, Romagnoli R, Soleymanlou N, Orsini B, Zamudio S, Paulesu L, Caniggia I (2007) Oxygen regulation of macrophage migration inhibitory factor in human placenta. Am J Physiol Endocrinol Metab 292:E272–E280

    Article  PubMed  CAS  Google Scholar 

  • Iwawaki T, Akai R, Yamanaka S, Kohno K (2009) Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci USA 106:16657–16662

    Article  PubMed  CAS  Google Scholar 

  • Jackson MR, Mayhew TM, Haas JD (1987) Morphometric studies on villi in human term placentae and the effects of altitude, ethnic grouping and sex of newborn. Placenta 8:487–495

    Article  PubMed  CAS  Google Scholar 

  • Jackson MR, Mayhew TM, Boyd PA (1992) Quantitative description of the elaboration and maturation of villi from 10 weeks of gestation to term. Placenta 13:357–370

    Article  PubMed  CAS  Google Scholar 

  • James JL, Stone PR, Chamley LW (2006a) The regulation of trophoblast differentiation by oxygen in the first trimester of pregnancy. Hum Reprod Update 12:137–144

    Article  PubMed  CAS  Google Scholar 

  • James JL, Stone PR, Chamley LW (2006b) The effects of oxygen concentration and gestational age on extravillous trophoblast outgrowth in a human first trimester villous explant model. Hum Reprod 21:2699–2705

    Article  PubMed  Google Scholar 

  • Jauniaux E, Burton GJ (2005) Pathophysiology of histological changes in early pregnancy loss. Placenta 26:114–123

    Article  PubMed  CAS  Google Scholar 

  • Jauniaux E, Burton GJ (2008) Placental circulations. In: Yagel S, Gembruch U, Silverman NH (eds) Fetal cardiology: embryology, genetics, physiology, echocardiography evaluation, diagnosis and perinatal management of cardiac diseases. Informa Healthcare, London, pp 41–56

    Chapter  Google Scholar 

  • Jauniaux E, Gulbis B (2000) Fluid compartments of the embryonic environment. Hum Reprod Update 6:268–278

    Article  PubMed  CAS  Google Scholar 

  • Jauniaux E, Jurkovic D, Campbell S (1991a) In vivo investigations of anatomy and physiology of early human placental circulations. Ultrasound Obstet Gynecol 1:435–445

    Article  PubMed  CAS  Google Scholar 

  • Jauniaux E, Burton GJ, Moscosco GJ, Hustin J (1991b) Development of the early placenta: a morphometric study. Placenta 12:269–276

    Article  PubMed  CAS  Google Scholar 

  • Jauniaux E, Watson AL, Hempstock J, Bao Y-P, Skepper JN, Burton GJ (2000) Onset of maternal arterial blood flow and placental oxidative stress; a possible factor in human early pregnancy failure. Am J Pathol 157:2111–2122

    Article  PubMed  CAS  Google Scholar 

  • Jauniaux E, Watson AL, Burton GJ (2001) Evaluation of respiratory gases and acid-base gradients in fetal fluids and uteroplacental tissue between 7 and 16 weeks. Am J Obstet Gynecol 184:998–1003

    Article  PubMed  CAS  Google Scholar 

  • Jauniaux E, Hempstock J, Greenwold N, Burton GJ (2003) Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies. Am J Pathol 162:115–125

    Article  PubMed  Google Scholar 

  • Jauniaux E, Hempstock J, Teng C, Battaglia F, Burton GJ (2005) Polyol concentrations in the fluid compartments of the human conceptus during the first trimester of pregnancy; maintenance of redox potential in a low oxygen environment. J Clin Endocrinol Metab 90:1171–1175

    Article  PubMed  CAS  Google Scholar 

  • Jiang B, Kamat A, Mendelson CR (2000) Hypoxia prevents induction of aromatase expression in human trophoblast cells in culture: potential inhibitory role of the hypoxia-inducible transcription ­factor Mash-2 (mammalian achaete-scute homologous protein-2). Mol Endocrinol 14:1661–1673

    Article  PubMed  CAS  Google Scholar 

  • Jirkovska M, Kubinova L, Janacek J, Moravcova M, Krejci V, Karen P (2002) Topological properties and spatial organization of villous capillaries in normal and diabetic placentas. J Vasc Res 39:268–278

    Article  PubMed  Google Scholar 

  • Jirkovska M, Janacek J, Kalab J, Kubinova L (2008) Three-dimensional arrangement of the capillary bed and its relationship to microrheology in the terminal villi of normal term placenta. Placenta 29:892–897

    Article  PubMed  CAS  Google Scholar 

  • Jones CJP, Fox H (1980) An ultrastructural and ultrahistochemical study of the human placenta in maternal pre-eclampsia. Placenta 1:61–76

    Article  PubMed  CAS  Google Scholar 

  • Kadyrov M, Kosanke G, Kingdom J and Kaufmann P (1998) Increased fetoplacental angiogenesis during first trimester in anaemic women. Lancet 352:1747–1749

    PubMed  CAS  Google Scholar 

  • Karimu AL, Burton GJ (1993) Star volume estimates of the intervillous gaps in the human placenta: How changes in umbilical arterial ­pressure might influence the maternal placental circulation. J Dev Physiol 19:137–142

    PubMed  CAS  Google Scholar 

  • Karimu AL, Burton GJ (1994) The effects of maternal vascular pressure on the dimensions of the placental capillaries. Br J Obstet Gynaecol 101:57–63

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann P (1981) Entwicklung der Plazenta. In: Becker V, Schiebler TH, Kubli F (eds) Die Plazenta des Menschen. Thieme, Stuttgart, pp 13–50

    Google Scholar 

  • Kaufmann P (1985) Basic morphology of the fetal and maternal circuits in the human placenta. Contrib Gynecol Obstet 13:5–17

    PubMed  CAS  Google Scholar 

  • Kaufmann P, Kingdom JCP (2000) Development of the vascular system in the placenta. In: Risau W, Rubanyi GM (eds) Morphogenesis of endothelium. Harwood Academic Publishers, Amsterdam, pp 255–275

    Google Scholar 

  • Kaufmann P, Scheffen I (1992) Placental development. In: Polin R, Fox W (eds) Fetal and neonatal physiology. WB Saunders, Philadelphia, pp 47–56

    Google Scholar 

  • Kaufmann P, Stark J, Stegner HE (1977) The villous stroma of the human placenta. 1. The ultrastructure of fixed connective tissue cells. Cell Tissue Res 177:105–121

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann P, Sen DK, Schweikhert G (1979) Classification of human placental villi. 1. Histology. Cell Tissue Res 200:409–423

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann P, Bruns U, Leiser R, Luckhardt M, Winterhager E (1985) The fetal vascularisation of term placental villi. II. Intermediate and terminal villi. Anat Embryol 173:203–214

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann P, Luckhardt M, Schweikhart G, Cantle SJ (1987) ­Cross-sectional features and three-dimensional structure of human placental villi. Placenta 8:235–247

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann P, Luckhardt M, Leiser R (1988) Three-dimensional representation of the fetal vessel system in the human placenta. Trophoblast Res 3:113–137

    Google Scholar 

  • Kaufmann P, Mayhew TM, Charnock-Jones DS (2004) Aspects of human fetoplacental vasculogenesis and angiogenesis. II. Changes during normal pregnancy. Placenta 25:114–126

    Article  PubMed  CAS  Google Scholar 

  • Kendall RL, Thomas KA (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90:10705–10709

    Article  PubMed  CAS  Google Scholar 

  • Khaliq A, Li XF, Shams M, Sisi P, Acevedo CA, Whittle MJ, Weich H, Ahmed A (1996) Localisation of placenta growth factor P1GF in human term placenta. Growth Factors 13:243–250

    Article  PubMed  CAS  Google Scholar 

  • Kiernan MF, Barrie A, Szkolar J, Mills TA, Wareing M (2010) Functional evidence for oxygen-sensitive voltage-gated potassium channels in human placental vasculature. Placenta 31:553–555

    Article  PubMed  CAS  Google Scholar 

  • Kilby MD, Afford S, Li XF, Strain AJ, Ahmed A, Whittle MJ (1996) Localisation of hepatocyte growth factor and its receptor (c-met) protein and mRNA in human term placenta. Growth Factors 13:133–139

    Article  PubMed  CAS  Google Scholar 

  • Kingdom JCP, Kaufmann P (1997) Oxygen and placental villous development: origins of fetal hypoxia. Placenta 18:613–621

    Article  PubMed  CAS  Google Scholar 

  • Kingdom JCP, Macara L, Krebs C, Leiser R, Kaufmann P (1997) Pathological basis for abnormal umbilical artery Doppler waveforms in pregnancies complicated by intrauterine growth restriction: a review. Trophoblast Res 10:291–309

    Google Scholar 

  • Knerr I, Schubert SW, Wich C, Amann K, Aigner T, Vogler T, Jung R, Dotsch J, Rascher W, Hashemolhosseini S (2005) Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions. FEBS Lett 579:3991–3998

    Article  PubMed  CAS  Google Scholar 

  • Kohnen G, Kertschanska S, Demir R, Kaufmann P (1996) Placental villous stroma as a model system for myofibroblast differentiation. Histochem Cell Biol 105:415–429

    Article  PubMed  CAS  Google Scholar 

  • Kosanke G, Kadyrov M, Korr H, Kaufmann P (1998) Maternal anemia results in increased proliferation in human placental villi. Trophoblast Res 11:339–357

    Google Scholar 

  • Krampl E, Lees C, Bland JM, Espinoza Dorado J, Moscoso G, Campbell S (2000) Fetal biometry at 43,00 m compared to sea level Peru. Ultrasound Obstet Gynecol 16:9–18

    Article  PubMed  CAS  Google Scholar 

  • Krebs C, Longo LD, Leiser R (1997) Term ovine placental vasculature: comparison of sea level and high altitude conditions by corrosion cast and histomorphometry. Placenta 18:43–51

    Article  PubMed  CAS  Google Scholar 

  • Kudo Y, Boyd CA, Sargent IL, Redman CW (2003) Hypoxia alters expression and function of syncytin and its receptor during trophoblast cell fusion of human placental BeWo cells: implications for impaired trophoblast syncytialisation in pre-eclampsia. Biochim Biophys Acta 1638:63–71

    Article  PubMed  CAS  Google Scholar 

  • Kupferminc MJ, Daniel Y, Englender T, Baram A, Many A, Jaffa AJ, Gull I, Lessing JB (1997) Vascular endothelial growth factor is increased in patients with preeclampsia. Am J Reprod Immunol 38:302–306

    Article  PubMed  CAS  Google Scholar 

  • Lando D, Gorman JJ, Whitelaw ML, Peet DJ (2003) Oxygen-dependent regulation of hypoxia-inducible factors by prolyl and asparaginyl hydroxylation. Eur J Biochem 270:781–790

    Article  PubMed  CAS  Google Scholar 

  • Lash GE, Otun HA, Innes BA, Bulmer JN, Searle RF, Robson SC (2006) Low oxygen concentrations inhibit trophoblast cell invasion from early gestation placental explants via alterations in levels of the urokinase plasminogen activator system. Biol Reprod 74:403–409

    Article  PubMed  CAS  Google Scholar 

  • Lash GE, Hornbuckle J, Brunt A, Kirkley M, Searle RF, Robson SC, Bulmer JN (2007) Effect of low oxygen concentrations on trophoblast-like cell line invasion. Placenta 28:390–398

    Article  PubMed  CAS  Google Scholar 

  • Lash GE, Naruse K, Innes BA, Robson SC, Searle RF, Bulmer JN (2010) Secretion of angiogenic growth factors by villous cytotrophoblast and extravillous trophoblast in early human pregnancy. Placenta 31:545–548

    Article  PubMed  CAS  Google Scholar 

  • Leach L (2002) The phenotype of the human materno-fetal endothelial barrier: molecular occupancy of paracellular junctions dictate permeability and angiogenic plasticity. J Anat 200:599–606

    Article  PubMed  Google Scholar 

  • Leach L, Lammiman MJ, Babawale MO, Hobson SA, Bromilou B, Lovat S, Simmonds MJ (2000) Molecular organization of tight and adherens junctions in the human placental vascular tree. Placenta 21:547–557

    Article  PubMed  CAS  Google Scholar 

  • Leach L, Babawale MO, Anderson M, Lammiman M (2002) Vasculogenesis, angiogenesis and the molecular organisation of endothelial junctions in the early human placenta. J Vasc Res 39:246–259

    Article  PubMed  CAS  Google Scholar 

  • Leach RE, Kilburn BA, Petkova A, Romero R, Armant DR (2008) Diminished survival of human cytotrophoblast cells exposed to hypoxia/reoxygenation injury and associated reduction of heparin-binding epidermal growth factor-like growth factor. Am J Obstet Gynecol 198:471 e1–471 e7, discussion 471 e7–471 e78

    Article  CAS  Google Scholar 

  • Lee MY, Huang JP, Chen YY, Aplin JD, Wu YH, Chen CY, Chen PC, Chen CP (2009) Angiogenesis in differentiated placental multipotent mesenchymal stromal cells is dependent on integrin alpha5beta1. PLoS One 4:e6913

    Article  PubMed  CAS  Google Scholar 

  • Leiser R, Luckhardt M, Kaufmann P, Winterhager E, Bruns U (1985) The fetal vascularisation of term human placental villi. I. Peripheral stem villi. Anat Embryol 173:71–80

    Article  PubMed  CAS  Google Scholar 

  • Leist M, Single B, Castoldi AF, Kühnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185:1481–1486

    Article  PubMed  CAS  Google Scholar 

  • Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683

    Article  PubMed  CAS  Google Scholar 

  • Levy R, Smith SD, Chandler K, Sadovsky Y, Nelson DM (2000) Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor. Am J Physiol Cell Physiol 278:C982–C988

    PubMed  CAS  Google Scholar 

  • Li XF, Charnock-Jones DS, Zhang E, Hiby S, Malik S, Day K, Licence D, Bowen JM, Gardner L, King A, Loke YW, Smith SK (2001) Angiogenic growth factor messenger ribonucleic acids in uterine natural killer cells. J Clin Endocrinol Metab 86:1823–1834

    Article  PubMed  CAS  Google Scholar 

  • Li B, Sharpe EE, Maupin AB, Teleron AA, Pyle AL, Carmeliet P, Young PP (2006) VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization. FASEB J 20:1495–1497

    Article  PubMed  CAS  Google Scholar 

  • Lofstedt T, Fredlund E, Holmquist-Mengelbier L, Pietras A, Ovenberger M, Poellinger L, Pahlman S (2007) Hypoxia inducible factor-2alpha in cancer. Cell Cycle 6:919–926

    Article  PubMed  Google Scholar 

  • Lopez-Barneo J, del Toro R, Levitsky KL, Chiara MD, Ortega-Saenz P (2004) Regulation of oxygen sensing by ion channels. J Appl Physiol 96:1187–1195

    Article  PubMed  CAS  Google Scholar 

  • Lyall F, Greer IA, Boswell F, Fleming R (1997) Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre-eclampsia. Br J Obstet Gynaecol 104:223–228

    Article  PubMed  CAS  Google Scholar 

  • Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88:9267–9271

    Article  PubMed  CAS  Google Scholar 

  • Malek A, Sager R, Schneider H (2001) Effect of hypoxia, oxidative stress and lipopolysaccharides on the release of prostaglandins and cytokines from human term placental explants. Placenta 22(Suppl A):S45–S50

    Article  PubMed  Google Scholar 

  • Manes C (2001) Human placental NAD(P)H oxidase: solubilization and properties. Placenta 22:58–63

    Article  PubMed  CAS  Google Scholar 

  • Many A, Roberts JM (1997) Increased xanthine oxidase during labour-implications for oxidative stress. Placenta 18:725–726

    Article  PubMed  CAS  Google Scholar 

  • Maruo T, Matsuo H, Murata K, Mochizuki M (1992) Gestational age-dependent dual action of epidermal growth factor on human placenta early in gestation. J Clin Endocrinol Metab 75:1362–1367

    Article  PubMed  CAS  Google Scholar 

  • Marx GF, Patel S, Berman JA, Farmakides G, Schulman H (1986) Umbilical blood flow velocity waveforms in different maternal positions and with epidural analgesia. Obstet Gynecol 68:61–64

    PubMed  CAS  Google Scholar 

  • Mayhew TM (2002) Fetoplacental angiogenesis during gestation is biphasic, longitudinal and occurs by proliferation and remodelling of vascular endothelial cells. Placenta 23:742–750

    PubMed  Google Scholar 

  • Mayhew TM (2008) Taking tissue samples from the placenta: an illustration of principles and strategies. Placenta 29:1–14

    Article  PubMed  CAS  Google Scholar 

  • Mayhew TM, Wadrop E (1994) Placental morphogenesis and the star volumes of villous trees and intervillous pores. Placenta 15:209–217

    Article  PubMed  CAS  Google Scholar 

  • Mayhew TM, Jackson MR, Haas JD (1986) Microscopical morphology of the human placenta and its effects on oxygen diffusion: a morphometric study. Placenta 7:121–131

    Article  PubMed  CAS  Google Scholar 

  • Mayhew TM, Wadrop E, Simpson RA (1994) Proliferative versus hypertrophic growth in tissue subcompartments of human placental villi during gestation. J Anat 184(Pt 3):535–543

    PubMed  Google Scholar 

  • Mayhew TM, Charnock-Jones DS, Kaufmann P (2004) Aspects of human fetoplacental vasculogenesis and angiogenesis. III. Changes in complicated pregnancies. Placenta 25:127–139

    Article  PubMed  CAS  Google Scholar 

  • Mayhew TM, Manwani R, Ohadike C, Wijesekara J, Baker PN (2007) The placenta in pre-eclampsia and intrauterine growth restriction: studies on exchange surface areas, diffusion distances and villous membrane diffusive conductances. Placenta 28:233–238

    Article  PubMed  CAS  Google Scholar 

  • Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658

    PubMed  CAS  Google Scholar 

  • Moll W (2003) Structure adaptation and blood flow control in the uterine arterial system after hemochorial placentation. Eur J Obstet Gynecol Reprod Biol 110:S19–S27

    Article  PubMed  Google Scholar 

  • Moore LG (2010) Uterine blood flow as a determinant of fetoplacental development. In: Burton GJ, Barker DJP, Moffett A, Thornburg T (eds) The placenta and human developmental programming. Cambridge University Press, Cambridge, pp 126–144

    Chapter  Google Scholar 

  • Moore LG, Shriver M, Bemis L, Hickler B, Wilson M, Brutsaert T, Parra E, Vargas E (2004) Maternal adaptation to high-altitude pregnancy: an experiment of nature–a review. Placenta 25(Suppl A):S60–S71

    Article  PubMed  CAS  Google Scholar 

  • Morasso MI, Grinberg A, Robinson G, Sargent TD, Mahon KA (1999) Placental failure in mice lacking the homeobox gene Dlx3. Proc Natl Acad Sci USA 96:162–167

    Article  PubMed  CAS  Google Scholar 

  • Murthi P, Hiden U, Rajaraman G, Liu H, Borg AJ, Coombes F, Desoye G, Brennecke SP, Kalionis B (2008) Novel homeobox genes are differentially expressed in placental microvascular endothelial cells compared with macrovascular cells. Placenta 29:624–630

    Article  PubMed  CAS  Google Scholar 

  • Natanson-Yaron S, Anteby EY, Greenfield C, Goldman-Wohl D, Hamani Y, Hochner-Celnikier D, Yagel S (2007) FGF 10 and sprouty 2 modulate trophoblast invasion and branching morphogenesis. Mol Hum Reprod 13:511–519

    Article  PubMed  CAS  Google Scholar 

  • Nelson DM, Johnson RD, Smith SD, Anteby EY, Sadovsky Y (1999) Hypoxia limits differentiation and up-regulates expression and activity of prostaglandin H synthase 2 in cultured trophoblast from term human placenta. Am J Obstet Gynecol 180:896–902

    Article  PubMed  CAS  Google Scholar 

  • Palmer ME, Watson AL, Burton GJ (1997) Morphological analysis of degeneration and regeneration of syncytiotrophoblast in first trimester villi during organ culture. Hum Reprod 12:379–382

    Article  PubMed  CAS  Google Scholar 

  • Palmer LA, Gaston B, Johns RA (2000) Normoxic stabilization of hypoxia-inducible factor-1 expression and activity: redox-dependent effect of nitrogen oxides. Mol Pharmacol 58:1197–1203

    PubMed  CAS  Google Scholar 

  • Panigel M, Myers RE (1972) Histological and ultrastructural changes in rhesus monkey placenta following interruption of fetal placental circulation by fetectomy or interplacental umbilical vessel ligation. Acta Anat 81:481–506

    Article  PubMed  CAS  Google Scholar 

  • Patel J, Landers K, Mortimer RH, Richard K (2010) Regulation of Hypoxia Inducible Factors (HIF) in hypoxia and normoxia during placental development. Placenta 31:951–957

    Article  PubMed  CAS  Google Scholar 

  • Pijnenborg R, Bland JM, Robertson WB, Dixon G, Brosens I (1981) The pattern of interstitial trophoblastic invasion of the myometrium in early human pregnancy. Placenta 2:303–316

    Article  PubMed  CAS  Google Scholar 

  • Piotrowicz B, Niebrój TK and Sieroñ G (1969) The morphology and histochemistry of the full term placenta in anaemic patients. Folia Histochemica et Cytochemica 7:435–444

    PubMed  CAS  Google Scholar 

  • Postigo L, Heredia G, Illsley NP, Torricos T, Dolan C, Echalar L, Tellez W, Maldonado I, Brimacombe M, Balanza E, Vargas E, Zamudio S (2009) Where the O2 goes to: preservation of human fetal oxygen delivery and consumption at high altitude. J Physiol 587: 693–708

    Article  PubMed  CAS  Google Scholar 

  • Postovit LM, Adams MA, Lash GE, Heaton JP, Graham CH (2002) Oxygen-mediated regulation of tumor cell invasiveness. Involvement of a nitric oxide signaling pathway. J Biol Chem 277: 35730–35737

    Article  PubMed  CAS  Google Scholar 

  • Pringle KG, Kind KL, Sferruzzi-Perri AN, Thompson JG, Roberts CT (2010) Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy. Hum Reprod Update 16:415–431

    Article  PubMed  CAS  Google Scholar 

  • Raijmakers MTM, Peters WHM, Steegers EAP, Poston L (2004) NAD(P)H oxidase associated superoxide production in human placenta from normotensive and pre-eclamptic women. Placenta 25(Suppl A):S85–S89

    Article  PubMed  CAS  Google Scholar 

  • Rajakumar A, Conrad KP (2000) Expression, ontogeny, and regulation of hypoxia-inducible transcription factors in the human placenta. Biol Reprod 63:559–569

    Article  PubMed  CAS  Google Scholar 

  • Rajakumar A, Michael HM, Daftary A, Jeyabalan A, Gilmour C, Conrad KP (2008) Proteasomal activity in placentas from women with preeclampsia and intrauterine growth restriction: implications for expression of HIF-alpha proteins. Placenta 29:290–299

    Article  PubMed  CAS  Google Scholar 

  • Ray PS, Jia J, Yao P, Majumder M, Hatzoglou M, Fox PL (2009) A stress-responsive RNA switch regulates VEGFA expression. Nature 457:915–919

    Article  PubMed  CAS  Google Scholar 

  • Redman CW, Sargent IL (2005) Latest advances in understanding preeclampsia. Science 308:1592–1594

    Article  PubMed  CAS  Google Scholar 

  • Reshetnikova OS, Burton GJ, Milovanov AP (1994) Effects of hypobaric hypoxia on the feto-placental unit; the morphometric diffusing capacity of the villous membrane at high altitude. Am J Obstet Gynecol 171:1560–1565

    Article  PubMed  CAS  Google Scholar 

  • Reshetnikova OS, Burton GJ, Milovanov AP, Fokin EI (1996) Increased incidence of placental chorangioma in high altitude pregnancies; hypobaric hypoxia as a possible aetiological factor. Am J Obstet Gynecol 174:557–561

    Article  PubMed  CAS  Google Scholar 

  • Reti NG, Lappas M, Huppertz B, Riley C, Wlodek ME, Henschke P, Permezel M, Rice GE (2007) Effect of high oxygen on placental function in short-term explant cultures. Cell Tissue Res 328:607–616

    Article  PubMed  CAS  Google Scholar 

  • Reuvekamp A, Velsing-Aarts FV, Poulina IE, Capello JJ, Duits AJ (1999) Selective deficit of angiogenic growth factors characterises pregnancies complicated by pre-eclampsia. Br J Obstet Gynaecol 106:1019–1022

    Article  PubMed  CAS  Google Scholar 

  • Reynolds SRM, Freese UE, Bieniarz J, Caldeyro-Barcia R, Mendez-Bauer C, Escarcena L (1968) Multiple simultaneous intervillous space pressures recorded in several regions of the hemochorial placenta in relation to functional anatomy of the fetal cotyledon. Am J Obstet Gynecol 102:1128–1134

    PubMed  CAS  Google Scholar 

  • Robin C, Bollerot K, Mendes S, Haak E, Crisan M, Cerisoli F, Lauw I, Kaimakis P, Jorna R, Vermeulen M, Kayser M, van der Linden R, Imanirad P, Verstegen M, Nawaz-Yousaf H, Papazian N, Steegers E, Cupedo T, Dzierzak E (2009) Human placenta is a potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout development. Cell Stem Cell 5:385–395

    Article  PubMed  CAS  Google Scholar 

  • Rolfo A, Many A, Racano A, Tal R, Tagliaferro A, Ietta F, Wang J, Post M, Caniggia I (2010) Abnormalities in oxygen sensing define early and late onset preeclampsia as distinct pathologies. PLoS One 5:e13288

    Article  PubMed  CAS  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  PubMed  CAS  Google Scholar 

  • Schaaps JP, Tsatsaris V, Goffin F, Brichant JF, Delbecque K, Tebache M, Collignon L, Retz MC, Foidart JM (2005) Shunting the intervillous space: new concepts in human uteroplacental vascularization. Am J Obstet Gynecol 192:323–332

    Article  PubMed  Google Scholar 

  • Schachter M, Foulds S (1999) Free radicals and the xanthine oxidase pathway. In: Grace PA, Mathie RT (eds) Ischaemia-reperfusion injury. Blackwell Science Ltd, Oxford, pp 137–147

    Google Scholar 

  • Schäffer L, Scheid A, Spielmann P, Breymann C, Zimmermann R, Meuli M, Gassmann M, Marti HM, Wenger RH (2003) Oxygen-regulated expression of TGF-β3, a growth factor involved in trophoblast differentiation. Placenta 24:941–950

    Article  PubMed  CAS  Google Scholar 

  • Scheffen I, Kaufmann P, Philippens L, Leiser R, Geisen C, Mottaghy K (1990) Alterations of the fetal capillary bed in the guinea pig placenta following long term hypoxia. In: Pijper J, Goldstick TK, Meyer D (eds) Oxygen transfer to tissue. Plenum Press, New York, pp 779–790

    Google Scholar 

  • Schiebler TH, Kaufmann P (1981) Reife Plazenta. In: Becker V, Schiebler TH, Kubli F (eds) Die Plazenta des Menschen. Thieme, Stuttgart, pp 51–111

    Google Scholar 

  • Schneider H (2000) Placental oxygen consumption. Part II: in vitro studies – a review. Placenta 21(Suppl A):S38–S44

    Article  PubMed  Google Scholar 

  • Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789

    Article  PubMed  CAS  Google Scholar 

  • Schuhmann RA (1982) Placentone structure of the human placenta. Bibl Anat 22:46–57

    PubMed  Google Scholar 

  • Schuhmann R, Stoz F, Maier M (1988) Histometric investigations in placentones (materno-fetal circulation units) of human placentae. Trophoblast Res 3:3–16

    Google Scholar 

  • Semenza GL (1998) Hypoxia-inducible factor 1; master regulator of O2 homeostasis. Curr Opin Genet Dev 8:588–594

    Article  PubMed  CAS  Google Scholar 

  • Sen DK, Kaufmann P, Schweikhart G (1979) Classification of placental villi. II. Morphometry. Cell Tissue Res 200:425–434

    Article  PubMed  CAS  Google Scholar 

  • Seval Y, Sati L, Celik-Ozenci C, Taskin O, Demir R (2008) The distribution of angiopoietin-1, angiopoietin-2 and their receptors tie-1 and tie-2 in the very early human placenta. Placenta 29:809–815

    Article  PubMed  CAS  Google Scholar 

  • Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66

    Article  PubMed  CAS  Google Scholar 

  • Shams M, Ahmed A (1994) Localization of mRNA for basic fibroblast growth factor in human placenta. Growth Factors 11:105–111

    Article  PubMed  CAS  Google Scholar 

  • Sharkey AM, Charnock-Jones DS, Boocock CA, Brown KD, Smith SK (1993) Expression of mRNA for vascular endothelial growth factor in human placenta. J Reprod Fertil 99:609–615

    Article  PubMed  CAS  Google Scholar 

  • Sharkey AM, Cooper JC, Balmforth JR, McLaren J, Clark DE, Charnock-Jones DS, Morris NH, Smith SK (1996) Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by pre-eclampsia. Eur J Clin Invest 26:1182–1185

    Article  PubMed  CAS  Google Scholar 

  • Shore VH, Wang TH, Wang CL, Torry RJ, Caudle MR, Torry DS (1997) Vascular endothelial growth factor, placenta growth factor and their receptors in isolated human trophoblast. Placenta 18:657–665

    Article  PubMed  CAS  Google Scholar 

  • Siman CM, Sibley CP, Jones CJ, Turner MA, Greenwood SL (2001) The functional regeneration of syncytiotrophoblast in cultured explants of term placenta. Am J Physiol Regul Integr Comp Physiol 280:R1116–R1122

    PubMed  CAS  Google Scholar 

  • Smith TG, Robbins PA, Ratcliffe PJ (2008) The human side of hypoxia-inducible factor. Br J Haematol 141:325–334

    Article  PubMed  CAS  Google Scholar 

  • Soleymanlou N, Wu Y, Wang JX, Todros T, Ietta F, Jurisicova A, Post M, Caniggia I (2005) A novel Mtd splice isoform is responsible for trophoblast cell death in pre-eclampsia. Cell Death Differ 12:441–452

    Article  PubMed  CAS  Google Scholar 

  • Soma H, Watanabe Y, Hata T (1995) Chorangiosis and chorangioma in three cohorts of placentas from Nepal, Tibet and Japan. Reprod Fertil Dev 7:1533–1538

    Article  PubMed  CAS  Google Scholar 

  • Somerset DA, Li XF, Afford S, Strain A, Ahmed A, Sangha RK, Whittle MJ, Kilby MD (1998) Ontogeny of hepatocyte growth factor (HGF) and its receptor (c-met) in human placenta – reduced HGF expression in intrauterine growth restriction. Am J Pathol 153:1139–1147

    Article  PubMed  CAS  Google Scholar 

  • Soothill PW, Nicolaides KH, Rodeck CH, Campbell S (1986) Effect of gestational age on fetal and intervillous blood gas and acid-base values in human pregnancy. Fetal Ther 1:168–175

    Article  PubMed  CAS  Google Scholar 

  • Tertemiz F, Kayisli UA, Arici A, Demir R (2005) Apoptosis contributes to vascular lumen formation and vascular branching in human placental vasculogenesis. Biol Reprod 72:727–735

    Article  PubMed  CAS  Google Scholar 

  • Todros T, Sciarrone A, Piccoli E, Guiot C, Kaufmann P, Kingdom J (1999) Umbilical Doppler waveforms and placental villous angiogenesis in pregnancies complicated by fetal growth restriction. Obstet Gynecol 93:499–503

    Article  PubMed  CAS  Google Scholar 

  • Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ (1998) Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol 179:1539–1544

    Article  PubMed  CAS  Google Scholar 

  • Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A, Schaaps JP, Cabrol D, Frankenne F, Foidart JM (2003) Over­expression of the soluble vascular endothelial growth factor ­receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 88:5555–5563

    Article  PubMed  CAS  Google Scholar 

  • Tu BP, Weissman JS (2004) Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol 164:341–346

    Article  PubMed  CAS  Google Scholar 

  • Tuuli MG, Longtine MS, Nelson DM (2011) Oxygen and trophoblast biology – a source of controversy. Placenta 32(Suppl 2):S109–S118

    Article  PubMed  CAS  Google Scholar 

  • Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N (1995) Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 373:702–705

    Article  PubMed  CAS  Google Scholar 

  • van Oppenraaij RH, Koning AH, Lisman BA, Boer K, van den Hoff MJ, van der Spek PJ, Steegers EA, Exalto N (2009) Vasculogenesis and angiogenesis in the first trimester human placenta: an innovative 3D study using an immersive virtual reality system. Placenta 30:220–222

    Article  PubMed  CAS  Google Scholar 

  • Velde EAt, Exalto N, Hesseling P, Linden HCvd (1997) First trimester development of human chorionic villous vascularization studied with CD34 immunohistochemistry. Hum Reprod 12:1577–1581

    Article  Google Scholar 

  • Voigt S, Kaufmann P, Schweikhart G (1978) Problems of distinction of normal, artificial, and pathological structures in mature human placental villi. II. Morphometrical studies on the influence of the mode of fixation (author’s transl). Arch Gynecol 226:347–362

    Article  PubMed  CAS  Google Scholar 

  • Vuckovic M, Ponting J, Terman BI, Niketic V, Seif MW, Kumar S (1996) Expression of the vascular endothelial growth factor receptor, KDR, in human placenta. J Anat 188:361–366

    PubMed  CAS  Google Scholar 

  • Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514

    Article  PubMed  CAS  Google Scholar 

  • Wareing M, Greenwood SL (2011) Review: potassium channels in the human fetoplacental vasculature. Placenta 32(Suppl 2):S203–S206

    Article  PubMed  CAS  Google Scholar 

  • Wheeler T, Elcock CL, Anthony FW (1995) Angiogenesis and the placental environment. Placenta 16:289–296

    Article  PubMed  CAS  Google Scholar 

  • Wigglesworth JS (1969) Vascular anatomy of the human placenta and its significance for placental pathology. J Obstet Gynaecol Br Commonw 76:979–989

    Article  PubMed  CAS  Google Scholar 

  • Wouters BG, Koritzinsky M (2008) Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 8:851–864

    Article  PubMed  CAS  Google Scholar 

  • Wu CC, Chao YC, Chen CN, Chien S, Chen YC, Chien CC, Chiu JJ, Linju Yen B (2008) Synergism of biochemical and mechanical ­stimuli in the differentiation of human placenta-derived multipotent cells into endothelial cells. J Biomech 41:813–821

    Article  PubMed  Google Scholar 

  • Wulff C, Wilson H, Dickson SE, Wiegand SJ, Fraser HM (2002) Hemochorial placentation in the primate: expression of vascular endothelial growth factor, angiopoietins, and their receptors throughout pregnancy. Biol Reprod 66:802–812

    Article  PubMed  CAS  Google Scholar 

  • Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto S, Takahashi N, Mori Y (2010) Chemical physiology of oxidative stress-activated TRPM2 and TRPC5 channels. Prog Biophys Mol Biol 103:18–27

    Article  PubMed  CAS  Google Scholar 

  • Yung HW, Calabrese S, Hynx D, Hemmings BA, Cetin I, Charnock-Jones DS, Burton GJ (2008) Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am J Pathol 173:451–462

    Article  PubMed  CAS  Google Scholar 

  • Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454:455–462

    Article  PubMed  CAS  Google Scholar 

  • Zhang EG, Smith SK, Baker PN, Charnock-Jones DS (2001) The regulation and localization of angiopoietin-1, -2, and their receptor Tie2 in normal and pathologic human placentae. Mol Med 7:624–635

    PubMed  CAS  Google Scholar 

  • Zhang EC, Burton GJ, Smith SK, Charnock-Jones DS (2002) Placental vessel adaptation during gestation and to high altitude: changes in diameter and perivascular cell coverage. Placenta 23:751–762

    PubMed  CAS  Google Scholar 

  • Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, Alitalo K, Damsky C, Fisher SJ (2002) Vascular endothelial growth factor ligands and receptors that regulate cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 160:1405–1423

    Article  PubMed  CAS  Google Scholar 

  • Ziche M, Maglione D, Ribatti D, Morbidelli L, Lago CT, Battisti M, Paoletti I, Barra A, Tucci M, Parise G, Vincenti V, Granger HJ, Viglietto G, Persico MG (1997) Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic. Lab Invest 76:517–531

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Prestwick Drive, La Jolla, CA, USA

    Kurt Benirschke M.D.

  2. Physiological Laboratory, University of Cambridge Centre for Trophoblast Research, Cambridge, UK

    Graham J. Burton M.D., D.Sc.

  3. Department of Pathology and Laboratory Medicine New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY, USA

    Rebecca N. Baergen M.D.

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Benirschke, K., Burton, G.J., Baergen, R.N. (2012). Architecture of Normal Villous Trees. In: Pathology of the Human Placenta. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-23941-0_7

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