Abstract: Sexual reproduction in the ocean necessitates only the combination of gametes, followed by absorption of nutrients and oxygen from the surrounding watery medium. As life moved from the sea to the land, reproductive strategies required compensation for the loss of this aquatic environment. For mammals and a few other animals, the solution to this problem was the development of the placenta, the means by which the fetus extracts nutrients from its environment. As the animals that used the placenta evolved from small rodent-like creatures with short gestations to larger animals with prolonged gestations, the demands of the developing fetus grew. Whereas the placenta of the fetal pig, with a gestational period of a little less than 4 months, can extract sufficient nutrients from the mother by simple diffusion across the uterus to the placenta, the human fetus needs a far more complex uteroplacental relationship. Several evolutionary solutions to the increased demands of fetuses can be observed.1Benirschke K Kaufmann P Pathology of the Human Placenta. 3d edition. Springer-Verlag, New York1995Crossref Google Scholar One approach was a larger placenta. For example, the chinchilla has a neonatal:placental weight ratio of 30:1, whereas the human has a 6:1 ratio. Another means to greater nutritional support for the fetus was to increase the surface area of contact between fetal circulation in the placenta and maternal circulation. The pig fetus has a diffuse placenta that makes contact with the mother's uterus by a simple folded contact. The human placenta, on the other hand, has a complex villous structure, similar to the sea anemone's tentacles waving in the sea, that greatly increases the contact surface area between the mother's blood space and the fetal circulation. Despite this increased fetal-maternal contact, the system is still rather inefficient. We can quantify this by considering the amount of oxygen in the maternal blood that enters the human placenta and the amount of oxygen in the fetal blood that leaves the placenta. Maternal blood has a pO2 of around 100, whereas the pO2 of umbilical vein blood is around 35 to 40. This represents an efficiency of only 35 to 40%. Therefore, it also became necessary to greatly increase the flow of maternal blood into the intervillous space during pregnancy.2Thornburg KL Jacobson SL Giraud GD Morton MJ Hemodynamic changes in pregnancy.Semin Perinatol. 2000; 24: 11-14Abstract Full Text PDF PubMed Google Scholar, 3Duvekot JJ Peeters LL Maternal cardiovascular hemodynamic adaptation to pregnancy.Obstet Gynecol Surv. 1994; 49: S1-S14Crossref PubMed Google Scholar Without this increased maternal blood flow, preterm birth and fetal loss occur.4Naeye RL Pregnancy hypertension, placental evidences of low uteroplacental blood flow, and spontaneous premature delivery.Hum Pathol. 1989; 20: 441-444Abstract Full Text PDF PubMed Google Scholar One of two mechanisms can increase maternal flow. increased total body blood flow or increased blood flow to the placental bed through the uterine spiral arteries. For the human, evolution has selected the latter mechanism, limiting the overall systemic effects that increased total body blood flow would produce. In the nonpregnant state the uterine vessels carry <1% of the maternal cardiac output.5Silver M Barnes RJ Comline RS Burton GJ Placental blood flow: some fetal and maternal cardiovascular adjustments during gestation.J Reprod Fertil Suppl. 1982; 31: 139-160PubMed Google Scholar This is not surprising in light of the fact that a nonpregnant women needs to maintain a uterus that weighs only 50 g. At term, these same vessels must support a uterus, placenta, and fetus that can weigh up to 5000 g. How can these vessels meet such a hemodynamic challenge? Doubling the number of vessels in the uterus, for example, would have only doubled the total amount of flow into the placenta. An understanding of fluid mechanics gives us insight into how such a significant increase in total blood flow can be achieved without increasing the total number of vessels in the uterus. Poiseuille's law of fluid flow in a cylinder states that flow is proportional to the radius to the fourth power.6Poston L The control of blood flow to the placenta.Exp Physiol. 1997; 82: 377-387PubMed Google Scholar Applying this law to the situation in the uterus, doubling the radius of a uterine vessel will increase the flow through that vessel 16 times. Comparison of vessels in the nonpregnant uterus to those at term reveals that these vessels can increase their radii by as much as tenfold. According to Poiseuille's law, this results in an increase in blood flow by a factor of 10,000! Clearly, the ability of uterine vessels to vary in diameter is a great advantage. The evolutionary problem then became how to convert small-caliber vessels in the nonpregnant state to large-caliber vessels during pregnancy, and then return them to their nonpregnant state and size when the pregnancy is completed. The answer lies in the relationship between the endometrium, uterine vessels, and invasive trophoblasts. Invasive trophoblasts are the key to the modulation of the state of the uterine vessels.7Kliman HJ Trophoblast infiltration.Reprod Med Rev. 1994; 3: 137-157Crossref Google Scholar These unique cells leave the placenta, penetrate the endometrium and upper layers of the myometrium, selectively permeate the uterine spiral arteries, and modify these vessels to yield widened, low-resistance vascular channels that carry the markedly increased maternal blood flow to the placenta. Enacting this scenario takes a very delicate balancing of conflicting biological needs between the mother and fetus. The fetus, on the one hand, requires its invasive trophoblasts to penetrate the mother's uterus aggressively in search of vessels to modify. The mother, on the other hand, must protect herself from the invasive trophoblasts, lest they completely penetrate her uterus, causing her to hemorrhage and bleed to death. Traditionally, two types of trophoblasts have been described: the cytotrophoblast and the syncytiotrophoblast. With the development of reproducible methods of trophoblast culture,8Kliman HJ Nestler JE Sermasi E Sanger JM Strauss JF Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae.Endocrinology. 1986; 118: 1567-1582Crossref PubMed Google Scholar improved markers of trophoblast synthetic activity,9Kliman HJ Feinberg RF Trophoblast differentiation.in: Barnea E Hustin J Jauniaux E The First Twelve Weeks of Gestation. Springer-Verlag, New York1992: 3-25Crossref Google Scholar and a deeper understanding of the functions that trophoblasts play in the uteroplacental unit,10Feinberg RF Kliman HJ Lockwood CJ Oncofetal fibronectin: a trophoblast "glue" for human implantation?.Am J Pathol. 1991; 138: 537-543PubMed Google Scholar, 11Feinberg RF Kao LC Haimowitz JE Queenan Jr, JT Wun TC Strauss JF Kliman HJ Plasminogen activator inhibitor types 1 and 2 in human trophoblasts: PAI-1 is an immunocytochemical marker of invading trophoblasts.Lab Invest. 1989; 61: 20-26PubMed Google Scholar, 12Damsky CH Fitzgerald ML Fisher SJ Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo.J Clin Invest. 1992; 89: 210-222Crossref PubMed Google Scholar, 13Fernandez PL Merino MJ Nogales FF Charonis AS Stetler Stevenson W Liotta L Immunohistochemical profile of basement membrane proteins and 72 kilodalton type IV collagenase in the implantation placental site: an integrated view.Lab Invest. 1992; 66: 572-579PubMed Google Scholar, 14Zhou Y Damsky CH Chiu K Roberts JM Fisher SJ Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts.J Clin Invest. 1993; 91: 950-960Crossref PubMed Google Scholar we now can identify more specific subsets of trophoblasts. These include the undifferentiated mononuclear precursor of all trophoblast forms, the cytotrophoblast; the endocrinologically active villous syncytiotrophoblast; the junctional trophoblast that attaches the anchoring villi to the maternal decidua at Nitabuch's layer; and the invasive intermediate trophoblast that migrates into the decidua, the myometrium, and finally the spiral arteries of the uterus (Figure 1).15Kliman HJ Trophoblast to human placenta.in: Knobil E Neill JD Encyclopedia of Reproduction. vol 4.. Academic Press, San Diego1999: 834-846Google Scholar The presence of invasive trophoblasts within the decidua and myometrium has been appreciated for some time,16Pijnenborg R Robertson WB Brosens I Dixon G Review article: trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals.Placenta. 1981; 2: 71-91Abstract Full Text PDF PubMed Google Scholar, 17Pijnenborg R Bland JM Robertson WB Brosens I Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy.Placenta. 1983; 4: 397-413Abstract Full Text PDF PubMed Google Scholar, 18Pijnenborg R The placentae bed.Hypertens Preg. 1996; 15: 7-23Crossref Google Scholar, 19Pijnenborg R Vercruysse L Verbist L Van Assche FA Interaction of interstitial trophoblast with placental bed capillaries and venules of normotensive and pre-eclamptic pregnancies.Placenta. 1998; 19: 569-575Abstract Full Text PDF PubMed Google Scholar but it is only relatively recently that researchers have attributed specific markers, and hence specific functional characteristics, to these cells. The first clear marker of the invasive trophoblast was described by Kurman and colleagues,20Kurman RJ Main CS Chen HC Intermediate trophoblast: a distinctive form of trophoblast with specific morphological, biochemical and functional features.Placenta. 1984; 5: 349-369Abstract Full Text PDF PubMed Google Scholar who demonstrated that first-trimester invasive trophoblasts react with anti-human placental lactogen antibodies. They coined the term "intermediate" invasive trophoblasts partly because of their intermediate size between cyto. and syncytiotrophoblasts. Feinberg et al11Feinberg RF Kao LC Haimowitz JE Queenan Jr, JT Wun TC Strauss JF Kliman HJ Plasminogen activator inhibitor types 1 and 2 in human trophoblasts: PAI-1 is an immunocytochemical marker of invading trophoblasts.Lab Invest. 1989; 61: 20-26PubMed Google Scholar demonstrated that these same cells express plasminogen activator inhibitor type 1, suggesting that intermediate invasive trophoblasts may use, in addition to the collagenases, the plasminogen activator system to perform their invasive function. More recently, Zhou et al14Zhou Y Damsky CH Chiu K Roberts JM Fisher SJ Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts.J Clin Invest. 1993; 91: 950-960Crossref PubMed Google Scholar, 21Zhou Y Fisher SJ Janatpour M Genbacev O Dejana E Wheelock M Damsky CH Human cytotrophoblasts adopt a vascular phenotype as they differentiate: a strategy for successful endovascular invasion?.J Clin Invest. 1997; 99: 2139-2151Crossref PubMed Google Scholar, 22Zhou Y Damsky CH Fisher SJ Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype: one cause of defective endovascular invasion in this syndrome?.J Clin Invest. 1997; 99: 2152-2164Crossref PubMed Google Scholar have shown that as trophoblasts leave the cell columns and enter the maternal space, they lose integrins for basement membrane interactions (possibly laminin) and gain integrins for fibronectin and type I collagen interactions. To protect the mother from the onslaught of invasive trophoblasts migrating toward the uterine spiral arteries, the endometrial stroma transforms itself into a dense cellular matrix known as the decidua.23Kearns M Lala PK Life history of decidual cells: a review.Am J Reprod Immunol. 1983; 3: 78-82Crossref PubMed Google Scholar The decidua impedes the movement of invasive trophoblasts both by forming a physical barrier to cell penetration and by generating a local cytokine milieu that promotes trophoblast attachment rather than invasion.7Kliman HJ Trophoblast infiltration.Reprod Med Rev. 1994; 3: 137-157Crossref Google Scholar, 24Graham CH Lala PK Mechanisms of placental invasion of the uterus and their control.Biochem Cell Biol. 1992; 70: 867-874Crossref PubMed Google Scholar, 25Graham CH Lysiak JJ McCrae KR Lala PK Localization of transforming growth factor-beta at the human fetal-maternal interface: role in trophoblast growth and differentiation.Biol Reprod. 1992; 46: 561-572Crossref PubMed Google Scholar, 26Clark DA Cytokines, decidua, and early pregnancy.Oxf Rev Reprod Biol. 1993; 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291: 133-148Crossref PubMed Scopus (147) Google Scholar Imbalances on either side of this equation can lead to abnormally limited or abnormally excessive invasion.23Kearns M Lala PK Life history of decidual cells: a review.Am J Reprod Immunol. 1983; 3: 78-82Crossref PubMed Google Scholar, 26Clark DA Cytokines, decidua, and early pregnancy.Oxf Rev Reprod Biol. 1993; 15: 83-111PubMed Google Scholar, 33Zhou Y Chiu K Brescia RJ Combs CA Katz MA Kitzmiller JL Heilbron DC Fisher SJ Increased depth of trophoblast invasion after chronic constriction of the lower aorta in rhesus monkeys.Am J Obstet Gynecol. 1993; 169: 224-229Abstract Full Text PDF PubMed Google Scholar, 40Lala PK Kearns M Immunobiology of the decidual tissue.Contrib Gynecol Obstet. 1985; 14: 1-15PubMed Google Scholar, 41Genbacev O Bass KE Joslin RJ Fisher SJ Maternal smoking inhibits early human cytotrophoblast differentiation.Reprod Toxicol. 1995; 9: 245-255Crossref PubMed Scopus (55) Google Scholar, 42DiFederico E Genbacev O Fisher SJ Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall.Am J Pathol. 1999; 155: 293-301Abstract Full Text Full Text PDF PubMed Google Scholar, 43Genbacev O DiFederico E McMaster M Fisher SJ Invasive cytotrophoblast apoptosis in pre-eclampsia.Hum Reprod. 1999; 14: 59-66Crossref PubMed Google Scholar The first signs of the decidualization reaction can be seen as early as day 23 (10 days after the peak of the luteinizing hormone surge. of the normal menstrual cycle, when the spiral arteries of the endometrium first become prominent.44Hendrickson MR Kempson RL Surgical pathology of the uterine corpus.Major Probl Pathol. 1979; 12: 36-98Google Scholar Over the next few days, the stromal cells surrounding the spiral arteries become increasingly eosinophilic and enlarged as the differentiating effect of progesterone transforms these cells into predecidual cells.45Tabanelli S Tang B Gurpide E In vitro decidualization of human endometrial stromal cells.J Steroid Biochem Mol Biol. 1992; 42: 337-344Crossref PubMed Google Scholar The progressive decidualization of the endometrial stroma in the later part of the menstrual cycle prepares the uterine lining for the presence of the invasive trophoblasts, but simultaneously closes the door to implantation.46Lessey BA Castelbaum AJ Buck CA Lei Y Yowell CW Sun J Further characterization of endometrial integrins during the menstrual cycle and in pregnancy.Fertil Steril. 1994; 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But how can a nonreceptive decidualized endometrium be returned to a receptive nondecidualized endometrium if no pregnancy occurs? The solution is menstruation.48Finn CA Why do women menstruate? Historical and evolutionary review.Eur J Obstet Gynecol Reprod Biol. 1996; 70: 3-8Abstract Full Text PDF PubMed Scopus (21) Google Scholar, 49Strassmann BI The evolution of endometrial cycles and menstruation.Q Rev Biol. 1996; 71: 181-220Crossref PubMed Google Scholar, 50Finn CA Menstruation: a nonadaptive consequence of uterine evolution.Q Rev Biol. 1998; 73: 163-173Crossref PubMed Google Scholar Menstruation, the breakdown and sloughing of the endometrial lining at the end of a hormonally driven cycle, is seen only in higher primates and humans.48Finn CA Why do women menstruate? 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This would help to explain the complex nature of the menstrual cycle with an estrogen-driven proliferative phase (to rebuild the lost endometrial tissue) followed by a progesterone-driven differentiation phase (that first opens the window of receptivity and later closes this window with the onset of decidualization).51Espey LL Ben Halim IA Characteristics and control of the normal menstrual cycle.Obstet Gynecol Clin North Am. 1990; 17: 275-298PubMed Google Scholar, 52Chabbert Buffet N Djakoure C Maitre SC Bouchard P Regulation of the human menstrual cycle.Front Neuroendocrinol. 1998; 19: 151-186Crossref PubMed Scopus (72) Google Scholar The morphological aspects of human trophoblast invasion have been examined in great detail over the last 20 years.11Feinberg RF Kao LC Haimowitz JE Queenan Jr, JT Wun TC Strauss JF Kliman HJ Plasminogen activator inhibitor types 1 and 2 in human trophoblasts: PAI-1 is an immunocytochemical marker of invading trophoblasts.Lab Invest. 1989; 61: 20-26PubMed Google Scholar, 17Pijnenborg R Bland JM Robertson WB Brosens I Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy.Placenta. 1983; 4: 397-413Abstract Full Text PDF PubMed Google Scholar, 31Zhou Y Genbacev O Damsky CH Fisher SJ Oxygen regulates human cytotrophoblast differentiation and invasion: implications for endovascular invasion in normal pregnancy and in pre-eclampsia.J Reprod Immunol. 1998; 39: 197-213Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 39Huppertz B Kertschanska S Demir AY Frank HG Kaufmann P Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and their inhibitors (TIMP) during trophoblast invasion in the human placenta.Cell Tissue Res. 1998; 291: 133-148Crossref PubMed Scopus (147) Google Scholar, 43Genbacev O DiFederico E McMaster M Fisher SJ Invasive cytotrophoblast apoptosis in pre-eclampsia.Hum Reprod. 1999; 14: 59-66Crossref PubMed Google Scholar, 53Pijnenborg R Bland JM Robertson WB Dixon G Brosens I The pattern of interstitial trophoblastic invasion of the myometrium in early human pregnancy.Placenta. 1981; 2: 303-316Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 54Pijnenborg R Robertson WB Brosens I Trophoblast invasion and formation of the basal plate in the human placenta.Bibl Anat. 1982; 22: 69-73PubMed Google Scholar, 55Robertson WB Brosens I Pijnenborg R De Wolf F The making of the placental bed.Eur J Obstet Gynecol Reprod Biol. 1984; 18: 255-266Abstract Full Text PDF PubMed Google Scholar, 56Robertson WB Brosens I Landells WN Abnormal placentation.Obstet Gynecol Annu. 1985; 14: 411-426PubMed Google Scholar, 57Lyall F Bulmer JN Kelly H Duffie E Robson SC Human trophoblast invasion and spiral artery transformation: the role of nitric oxide.Am J Pathol. 1999; 154: 1105-1114Abstract Full Text Full Text PDF PubMed Google Scholar, 58Lim KH Zhou Y Janatpour M McMaster M Bass K Chun SH Fisher SJ Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia.Am J Pathol. 1997; 151: 1809-1818PubMed Google Scholar Since it is difficult to reliably obtain human material before 4 weeks of gestation, much of our morphological understanding of the earliest phases of trophoblast invasion has been extrapolated from monkey material.59Blankenship TN Enders AC King BF Trophoblastic invasion and the development of uteroplacental arteries in the macaque: immunohistochemical localization of cytokeratins, desmin, type IV collagen, laminin, and fibronectin.Cell Tissue Res. 1993; 272: 227-236Crossref PubMed Scopus (82) Google Scholar, 60Blankenship TN Enders AC King BF Trophoblastic invasion and modification of uterine veins during placental development in macaques.Cell Tissue Res. 1993; 274: 135-144Crossref PubMed Google Scholar, 61Enders AC Welsh AO Structural interactions of trophoblast and uterus during hemochorial placenta formation.J Exp Zool. 1993; 266: 578-587Crossref PubMed Google Scholar, 62Enders AC King BF Early stages of trophoblastic invasion of the maternal vascular system during implantation in the macaque and baboon.Am J Anat. 1991; 192: 329-346Crossref PubMed Scopus (75) Google Scholar Examination of monkey implantation sites has revealed that trophoblasts begin to migrate down into the maternal spiral arteries as early as 10 days after fertilization, and at 14 days, many of the spiral arteries beneath the conceptus are totally occluded.62Enders AC King BF Early stages of trophoblastic invasion of the maternal vascular system during implantation in the macaque and baboon.Am J Anat. 1991; 192: 329-346Crossref PubMed Scopus (75) Google Scholar The specificity of this vascular interaction is revealed by the fact that no such invasion takes place in the veins. Do human trophoblasts behave in the same fashion? This question has been more difficult to answer, and addressing it has demanded varied approaches. Hustin and Schaaps, using anatomical and ultrasonographic approaches, suggested that there is in fact trophoblast plugging of the maternal spiral arteries and a coincident decrease in maternal perfusion of intervillous space until 12 weeks of gestation.63Hustin J Schaaps JP Echographic and anatomic studies of the maternotrophoblastic border during the first trimester of pregnancy.Am J Obstet Gynecol. 1987; 157: 162-168Abstract Full Text PDF PubMed Google Scholar Rodesch et al64Rodesch F Simon P Donner C Jauniaux E Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy.Obstet Gynecol. 1992; 80: 283-285PubMed Google Scholar then hypothesized that it is critical that maternal blood flow to the embryo be limited very early in gestation to protect the conceptus from excessively high oxygen levels during critical early stages of differentiation. This concept was supported by Coppens et al,65Coppens M Loquet P Kollen M De Neubourg F Buytaert P Longitudinal evaluation of uteroplacental and umbilical blood flow changes in normal early pregnancy.Ultrasound Obstet Gynecol. 1996; 7: 114-121Crossref PubMed Google Scholar whose study of serial ultrasounds on normal pregnant women between 8 and 14 weeks showed no uteroplacental blood flow in the first trimester but a significant increase at approximately 12 weeks, which reached maximal levels at 14 weeks. More recently, Burton et al critically examined the Boyd Collection, 12 early-pregnancy hysterectomy specimens ranging from 43 to 130 days of gestation housed in the Department of Anatomy at the University of Cambridge, and showed that there was significant blockage of the maternal spiral arterioles by trophoblasts at points of contact with the intervillous space between 6 and 8 weeks, but that this blockage was gradually eliminated between 8 and 12 weeks of gestation.66Burton GJ Jauniaux E Watson AL Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited.Am J Obstet Gynecol. 1999; 181: 718-724Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar Despite its teleological attractiveness, the first trimester low-flow concept has not been universally accepted.67Kurjak A Kupesic S Hafner T Kos M Kostovic-Knezevic L Grbesa D Conflicting data on intervillous circulation in early pregnancy.J Perinat Med. 1997; 25: 225-236Crossref PubMed Google Scholar, 68Valentin L Sladkevicius P Laurini R Soderberg H Marsal K Uteroplacental and luteal circulation in normal first-trimester pregnancies: Doppler ultrasonographic and morphologic study.Am J Obstet Gynecol. 1996; 174: 768-775Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 69Moll W Invited commentary: absence of intervillous blood flow in the first trimester of human pregnancy.Placenta. 1995; 16: 333-334Abstract Full Text PDF PubMed Google Scholar The controversy over this issue, however, seems to have been settled recently with the use of an advanced oxygen sensing probe. In this issue of The American Journal of Pathology, Jauniaux et al70Jauniaux E Watson AL Hempstock J Bao Y-P Skepper JN Burton GJ Onset of maternal arterial bloodflow and placental oxidative stress: a possible factor in human early pregnancy failure.Am J Pathol. 2000; 157: 3251-3262Abstract Full Text Full Text PDF Google Scholar report the direct documentation of a significant increase in placental intervillous oxygen tension, and hence maternal perfusion of the placenta, between 8 and 12 weeks of gestation. This article also reports that, coincident with this increased perfusion and oxygen tension within the placenta between 8 and 12 weeks, there is a corresponding increa