Angiogenesis and Villous
Maldevelopment of the Placenta
Introduction
The placenta has long been thought
to be a specific human structure. In modern times, however, it has become clear
that the human chorioallantoic placenta represents one of three basic types of
placentation (chorionic, chorioallantoic, yolksac placentation) which occur in
all mammals.1
The fully developed villous
hemochorial placenta appears to be almost completely composed of fetal blood
vessels which present an extensive capillary bed to the circulating maternal
blood for physiologic exchange related to fetal respiration, alimentation and
elimination.1
An assessment of placental pathology is useful for couples in
resolving issues arising from pregnancy complications, including perinatal
loss. It is also useful to clinicians for determining the underlying mechanisms
leading to pregnancy complications and for guiding future investigations and
interventions relating to pre-pregnancy counselling and pregnancy care.
Placental pathology can correlate with adverse neonatal and, particularly,
neurodevelopmental outcomes, even in the normally grown infant. Despite this,
very few studies have examined the relationship between placental pathology and
neonatal outcomes in a large population. Also, the
placental pathology report often arrives weeks or months after the delivery, at
which time it is of little use in guiding early neonatal care.2
On microscopic
examination to placenta, we can to see villous maldevelopment of placenta which
due to hypoxia. Villous maldevelopment of placenta are closely related to angiogenesis,
so we explain both of them on this script.
Angiogenesis
Because of the obvious importance of formation of vessels
for the understanding of decisive steps of villus development, some general
principles of vasculogenesis and angiogenesis as well as the respective
findings in the placenta shall be summarized here. According to Folkman and
Shing (1992), Risau and Flamme (1995), and Risau (1997), formation of vessels can
be subdivided in two processes that differ regarding mechanisms and control:
• Vasculogenesis involves
de novo formation of blood vessels from mesodermally derived precursor cells. Throughout
placentation, it takes place during the development of the first villous
vessels at the transition from secondary to the tertiary villous stage (from
day 18 through about day 35), and later in pregnancy during formation of mesenchymal
villi out of immature intermediate ones.
• Angiogenesis is the expansion
of a preexisting vessel bed and involves creation of new vessel branches from preexisting
ones as well as longitudinal growth of vessels.3
Throughout placentation it is the principal mechanism for the
development of the vascular supply of immature intermediate villi, stem villi,
mature intermediate villi, and terminal villi. Placental angiogenesis must be
further subdivided regarding its mechanisms and the geometry of the resulting vascular
bed (Kingdom & Kaufmann, 1997; Kaufmann & Kingdom, 2000; Charnock-Jones
et al., 2004) into of the following categories:
• Branching
angiogenesis: This term describes a pattern in which multiple
sprouting of microvessels produces a complex, multiply branched capillary web.
This is the principal type of angiogenesis from day 32 until about week 24
during development of mesenchymal and immature intermediate villi.
• Nonbranching
angiogenesis: In this type of angiogenesis branching by sprouting is the
exception. Rather, the vascular bed expands by elongation of existing capillary
loops. This mode of angiogenesis starts at about week 24 when mesenchymal villi
start developing into mature intermediate villi and the latter start producing
terminal villi. It lasts until term. Under pathologic conditions it may become
the only mode of angiogenesis. Under normal conditions it takes place in
combination with branching angiogenesis.3
Angiogenesis refers to the
formation of new vascular beds, and is a critical process for normal tissue
growth and development. Although numerous factors have been implicated in
angiogenesis, recent observations, including gene knockout studies in mice,
have led to the identification of the major factors regulating the angiogenic
process, including those that occur during placental vascularization.4,5
These
angiogenic factors include the vascular endothelial growth factor (VEGF),
fibroblast growth factor (FGF), and the angiopoietin (ANG) protein families, as
well as their respective receptors. That recent studies have suggested that
VEGF and FGF are major angiogenic growth factors of the placenta is not
surprising because these two families of proteins probably account for most of the
heparin-binding angiogenic activity produced by both ovarian and placental tissues.4,5
Oxygen
and Oxygen-Controlled Growth Factors as Regulators of Villous and Vascular
Development
Only a little is known concerning the control of villous development.
On the other hand, a broad variety of pathologic conditions, such as genetic
abnormalities but also such as diabetes mellitus, maternal hypertension, maternal
anemia or pregnancy in high altitude, rhesus incompatibility, and smoking
during pregnancy, severely affect villous and fetoplacental vascular
development. This list suggests that the villous and vascular maturational processes
are influenced not only by genes but also by endocrine, metabolic, and
environmental parameters. From these, only the role of oxygen has been studied
in some more detail. The special role of oxygen in the placenta when discussing
effects of oxygen in the placenta, one should be aware of the special role of this
gas in the placenta.3,6,7
First, transplacental oxygen transfer is only one of many
villous functions; however, its particular importance becomes evident from the
fact that it is nearly the only villous function that, upon disturbance, within
a short period of time may cause fetal death. Because of this, it is not
surprising that the maternal oxygen supply to the placenta has a stronger
impact on villous growth and differentiation than any other known parameter.3
Second and even more importantly, in most organs the
interactions among density of vascularization, tissue oxygenation, and
capillary growth follow the same pattern: a low degree of local vascularization
results in insufficient oxygen delivery to this tissue. The resulting tissue
hypoxia stimulates capillary growth and thus improves capillary density and
local tissue oxygenation. On the other hand, optimum capillarization of a
tissue under otherwise normal conditions guarantees a high tissue oxygenation and
this, in turn, will block further angiogenesis. By contrast, in placental villi
tissue oxygenation appears to be inversely related to the numerical density of
fetal capillaries since, rather than delivering oxygen to the surrounding
tissue, the latter extract it from the villi (Kingdom & Kaufmann, 1997).3
• Consequently, a low numerical density of
fetal capillaries because of reduced oxygen extraction by the fetal circulation,
results in increasing intraplacental oxygen levels (Todros et al., 1999; Sibley
et al., 2002), which, in turn, may negatively impact on the already poor
vascularization (Charnock-Jones et al, 2004).
• And under otherwise
constant conditions, high numerical densities of capillaries, resulting in high
oxygen extraction by the fetal circulation, would lower intraplacental oxygen
tensions (Todros et al., 1999; Sibley et al., 2002) and thus further stimulate
growth of the already well-developed capillary bed (Charnock-Jones et al.,
2004). It is evident that, when exceeding certain limits, both situations are
predetermined to develop vicious circles.3
Types of
Hypoxia and Its Effects on Villous Development
Because of the above-mentioned inverse relationship between the
degree of capillarization and the level of tissue oxygenation, the term hypoxia
in pregnancy often causes confusion. This is particularly true when the hypoxic
compartment is not exactly defined. Does the hypoxia relate to mother, uterus,
placenta, and the fetus, or to uterus, placenta, and fetus, or only to the
fetus? 3
Based on a respective international symposium 1996 in Banff
1997):
1. In preplacental
hypoxia, the mother, the placenta, and the fetus are hypoxic. Underlying pathologies include pregnancy at
high altitude (Jackson et al., 1987; Reshetnikova et al., 1993), maternal
anemia (Piotrowicz et al., 1969; Beischer et al., 1970; Kadyrov et al., 1998),
and cyanotic maternal cardiac diseases. In this condition, the peripheral
placental villi show increased branching angiogenesis with formation of richly
branched but shorter terminal capillary loops. These human data are consistent
with animal experiments in chronically hypoxic guinea pigs (Scheffen et al.,
1990) and chronically
hypoxic sheep (Krebs et al., 1997), in which both demonstrated increased
branching angiogenesis. Interestingly, in the guinea pig, capillary diameters were
reduced under these conditions (Bacon et al., 1984; Scheffen et al., 1990),
whereas they were increased in the sheep (Krebs et al., 1997). At the present
time, however, we do not understand which factors are responsible for
controlling capillary diameter in the human placenta.
2. In uteroplacental
hypoxia (e.g., preeclampsia with preserved umbilical end-diastolic
flow), maternal oxygenation is normal, but because of impaired uteroplacental
circulation (Alvarez et al., 1970; for review, see Brosens, 1988), the placenta
and fetus are both hypoxic. In this situation, peripheral placental villi
similarly show the formation of richly branching capillary networks and fetal blood flow impedance is normal or
even reduced (Kiserud et al., 1994; Hitschold et al., 1996). Preliminary
Western blot data show increased expression of VEGF and reduced PlGF values in
placentas of comparable cases (Ahmed et al., 1997), suggesting that placental
VEGF expression was upregulated in vivo and caused the changes in angiogenesis.
3. In postplacental
hypoxia (e.g., IUGR with absentumbilical end-diastolic flow), the fetus is hypoxic whereas the mother is
normoxic and the placenta may show even higher pO2 levels than normal, a
situation described as placental hyperoxia (Macara et al., 1996; Kingdom &
Kaufmann, 1997; for commentary, see Ahmed & Kilby, 1997). In this
situation, the terminal villus capillaries are poorly developed, capillary
branching is virtually absent and the
resulting fetoplacental flow impedance is considerably increased. Perinatal
mortality is more than 40% in these circumstances and survivors of neonatal
intensive care are at risk of neurodevelopmental handicap. Similar situations occur
in locally restricted parts of the placenta as a consequence of fetoplacental
vessel obstruction (Panigel & Myers, 1972; Fox, 1997). Preliminary Western
blot data in postplacental hypoxia suggest a pattern of angiogenic growth
factor expression in the placenta very different from that of preeclampsia with
preserved umbilical enddiastolic flow, namely, a reduction of VEGF expression and
relative dominance of PlGF (Ahmed et al., 1997).3,8
Several data support the view that the three variables described
above, (1) intraplacental oxygen partial pressure, (2) the balance between VEGF
and PlGF expression, and (3) the balance between branching and nonbranching
angiogenesis, depend on each other:
• In normal first
trimester pregnancy, physiologic intraplacental hypoxia favors VEGF expression
and branching angiogenesis.
• In normal third
trimester pregnancy, increased intraplacental pO2 results in a slight
prevalence of PlGF expression and dominating but not exclusive nonbranching
angiogenesis.
• In several pathologic
conditions of third trimester pregnancies, severe intraplacental hypoxia
results in prevalence of VEGF expression and marked branching angiogenesis.
• Elevated placental
oxygen pressures in severe early onset IUGR pregnancies (postplacental hypoxia)
are combined with the dominance of PlGF expression and complete absence of
branching angiogenesis in terminal villi.3
Classification of Villous Maldevelopment
The histopathology of villous maldevelopment is based on the
light microscopy of paraffin sections. Thus, the normal and pathologic features
of the placenta are usually described in terms of the two dimensions apparent
by light microscopy. These two dimensional findings very often do not reflect
the underlying three-dimensional malformation of villi.3
Based on these considerations, the following sections briefly
consider typical cases of villous maldevelopment and their three-dimensional
branching patterns and the diagnostic problems they cause in histologic
sections. The primary finding in placentas with villous maldevelopment is an
abnormal numerical composition of otherwise largely normal villous types
(Kaufmann et al., 1987):
• This is true for
immature intermediate villi and the mesenchymal villi branching off, and for
the mature intermediate villi and the terminal villi branching off. The villous
trees in the case of villous maldevelopment differ from the mature villous
trees at term by predominance of only one of these villous types at the expense
of others. Furthermore, they differ concerning the type of capillarization of
terminal villi.
• In contrast, the
structure and the number of stem villi seem to be largely independent of the
pathologic conditions. Rather, they are influenced by the stage of maturation
(Macara et al., 1995; Todros et al., 1999). Therefore, even in cases of severe
villous maldevelopment, they can be easily used for determination of gestational
age (Kaufmann & Castellucci, 1995).3
Systematic analysis of the various cases of villous
maldevelopment has shown that the balance among the various villous types is
affected mainly by two different factors: the degree of placental maturation
(Castellucci et al., 1990), and the degree of oxygenation (Macara et al., 1996;
Kingdom & Kaufmann, 1997; Todros et al., 1999).3,8
Figure 3 summarizes the resulting types of maldevelopment as a
diagnostic aid:
1. The vertical axis of
the diagram represents the degree of maturation, resulting in changes in
numerical composition of the villous trees. From the first trimester (top)
until term (bottom), a developmental shift occurs from immature intermediate
villi toward mature intermediate and finally terminal villi.
2. The horizontal axis of
the diagram represents the degree and type of fetoplacental angiogenesis,
controlled by intraplacental oxygen levels. The fetoplacental angiogenesis influences
the numbers and shapes of terminal villi.
3. The left route of
maturation represents villous features resulting from placental oxygenation
that is better than normal (postplacental hypoxia). It is characterized
by the predominance of nonbranching angiogenesis resulting in poorly developed,
long, filiform terminal villi with long, largely unbranched capillary loops.
4. The right route of
maturation is the result of intraplacental hypoxia (preplacental hypoxia
and uteroplacental hypoxia). The low oxygen levels induce branching
angiogenesis, resulting in clusters of richly developed, short, highly
branched and notched terminal villi, showing intense Tenney-Parker changes.
5. The intermediate route
of villous maturation is the result of normal oxygenation of the placenta.
It is characterized by a balance between branching and nonbranching angiogenesis
in terminal villi. The latter are grape-like in shape and poorly branched. Large
numbers of such fungus-shaped terminal villi branch off from long, multiply
bending mature intermediate villi.3,8
Villous Maturation Score
In our experience, villous cross-sectional patterns are
difficult to define. Moreover, descriptions provided by different
histopathologists are rarely comparable. In our hands, a simple two-digit code
(villous maturation score) proved to be useful. It summarizes the developmental
status of the villous trees including its numerical composition of the various villous
types as well as the kind of terminal villous capillarization. As discussed
earlier, number and differentiation of stem villi remain unconsidered.3
00 signifies uniform predominance of immature intermediate villi.
11 codes for general predominance of mature intermediate villi.
22 characterizes normally matured villous trees composed of
normally capillarized mature intermediate and terminal villi.
33 denotes predominance of clustered terminal villi connected to
each other by intense syncytial knotting, pointing to branching angiogenesis
caused by preplacental or uteroplacental hypoxia.
44 codes for predominance of loosely arranged, extremely small, filiform
terminal villi, resulting from nonbranching angiogenesis.3
Scores with mixed digits such as 23, 32, 01,
or 40 describe features intermediate between the above extremes, the
dominating feature represented by the first digit and the secondary feature by
the second digit. For example, the score 23 codes for a more or less
normally matured villous tree with a slight touch of Tenney-Parker changes,
pointing to the existence of very mild hypoxia; in contrast, the score 32
denotes a similar situation with more pronounced Tenney-Parker changes.3
Using this score, the different pathways of villous development
and maldevelopment can be described as follows (see Table 1):
• The normal maturation
of villous trees described by this score starts with 00 [pregnancy
weeks 8–23 postmenstruation (p.m.)] and proceeds via 01 (weeks 24–28), 10
(weeks 29–32), 11 (weeks 32–34), 12 (weeks 34–36), 21 (weeks
36–37) to 22 (weeks 38– 41). The scores 21 and 22 represent
the normal range of villous maturational patterns at term. If delivery is
delayed (prolonged pregnancies), the villi may even reach excessive degrees of
branching and nonbranching angiogenesis with respective terminal villus
formation, summarized by the score 34 or 43, depending on the
prevailing type of angiogenesis.
• Persisting villous
immaturity can be described by the actual villous maturational stage as
compared to the age-appropriate maturational score, given in parentheses: the
score 00 (21) codes for a slightly preterm delivered placenta
(weeks 36–37; expected ageappropriate score, 21) composed of immature
intermediate villi, resembling a placenta from week 23 or earlier; the score 11
(22) codes for a placenta delivered at term, composed of stem and
mature intermediate villi, but largely lacking terminal villi, thus resembling
a placenta about weeks 32 to 34.
• Accelerated villous
maturation can be coded accordingly by characterizing the actual
developmental status as compared to the score expected for that particular
stage of pregnancy (in parentheses): the score 22 (12) describes
a structurally fully mature placenta delivered between weeks 34 and 36 (preterm
maturation, maturitas praecox placentae); the score 34 (22) codes
for a placenta delivered at term, but displaying “hypermature” features composed
of a mixture of enhanced branching and nonbranching angiogenesis.3
The developmental pathways resulting from abnormal degrees of placental
oxygenation can also be characterized by the villous maturation score (Table 2):
• Villous trees in severely
hypoxic placentas (preplacental and uteroplacental hypoxia), such as
maternal anemia, high altitude, or preeclampsia, are characterized by scores
proceeding from 00 via 03 and 30 to 33: The respective
histologic features show syncytial knotting (Tenney-Parker changes) clearly
exceeding normal degrees. Typically, in this developmental pathway mature
intermediate villi (coded by the digit 1) do not dominate the sections
in any stage.
• Less severe cases of
placental hypoxia result in villous features with less expressive knotting
and are coded by 32 or 23, the latter entity still belonging to
the normal range of full-term placentas.
• Cases of severe
postplacental hypoxia (e.g., IUGR with absent end-diastolic flow in the
umbilical arteries) are coded by scores proceeding from 00 via 04 and
40 to 44. The typical histologic features comprise increased
numbers of filiform terminal villi of minimum diameters with absence of
capillary branching. Also in these cases, the paucity of mature intermediate
villi is highly characteristic; at the transition from the second to the third
trimester, immature intermediate villi mix with terminal villi (stages 04 or
40).
• Less severe cases of
postplacental hypoxia lead to a mixture of normally matured terminal villi
with filiform terminal villi resulting from nonbranching angiogenesis, coded by
42 to 24, the latter feature still belonging to the normal
full-term range of villous development.3
Clearly, not all cases of villous maldevelopment can be coded
accordingly. This condition is particularly valid for those abnormalities in
which the quality of villous differentiation is affected rather than the
numerical composition of the villous trees, including the types of
angiogenesis.3
This villous maturation score is not the first attempt to
classify villous maldevelopment. In table 3, Kurt Benirschke and friends have
tried to compare their classification with the terminologies introduced by
other authors (Becker, 1981; Vogel, 1984, 1996; Schweikhart, 1985; Becker &
Röckelein, 1989).3
References
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and Pathogenesis of Placental Infarcts. Drukkerij Van Denderen.
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Placental Pathology and Clinical Outcomes in a Cohort of Infants Admitted
to a Neonatal Intensive Care Unit. Obstetric Gynaecology Journal. 2007. Volume
29. Number 4. Page 315-323.
- Benirschke K. Kaufmann P. Baergen
R.N. Pathology of The Human Placenta. Springer.
- Reynolds L.P. Redmer D.A.
Angiogenesis in The Placenta. Biology of Reproduction Journal. 2001.
Volume 64. Page 1033-1040.
- Loganath A. Peh K.L. Wong Y.C. Angiogenesis
in Placenta From Normal and Pathological Pregnancies. Department of
Obstetric and Gynaecology.
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Associated with Maturation Abnormalities and Late Intrauterine Fetal
Death. Department of Pathology. UMC
- Stallmach T. Hebisch G. Meier K.
Rescue by Birth: Defective Placental Maturation and Late Fetal Mortality.
Obstetric Gynaecology Journal. 2001. Volume 97. Number 4. Page 505-509.
- Baergen R.N. Manual of Benirschke
and Kaufmann’s Pathology of The Human Placenta. Springer.
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