Utero-Placental Vascular Developmentand
Placental Function1r2
Lawrence P. Reynolds3 and Dale A. Redmer
Department of Animal and Range Sciences, NorthDakota
ABSTRACT:
The rate of fetal growth and subsequent birth weight are major determinants of postnatal survival and growth. Because the placenta is the
organ through which respiratory gases, nutrients, and
wastesaretransported
between thematernaland
fetalsystems,itsprimary
function is t o supply the
metabolic substrates necessary
support
to fetal
growth. Placental growth and development, therefore,
are critical for normal fetal growth and development.
During the last half of gestation in mammals, growth
of thefetusis
exponential,whereasutero-placental
growth slows or ceases. Nevertheless, unless placental
transport capacitykeeps pace with the continually
increasing demands of the fetus, fetal growth will be
compromised. Studies over the last two decades have
KeyWords:
State University,Fargo
58105
shown that placental transport capacity does indeed
keep pace with fetal growth. This increase in placental
function can be accounted for primarily by continual
increases in placental (uterine and umbilical)
blood
flows, associated with increased placental vascularity.
Placental vascular growth and development, in turn,
are probably regulated by angiogenic factors produced
by the placental tissues themselves. These placental
angiogenic factors are produced primarily by the
maternal placental tissues, are heparin-binding, and
seem to be related to the fibroblast growth factor
family. Further elucidation of the factors responsible
for placentalgrowth
and vascular development is
critical for an improved understanding of uteroplacental-fetal interactions, which result in delivery of
a healthy offspring.
Fetus,Placenta,Growth,
Angiogenesis, Angiogenic Factors
J. Anim. Sci. 1995. 73:1839-1851
Introduction
The exact cooperation of the embryo’s allantoic
vasculature
and
the
trophoblast
with
the
mother’s endometrial vasculature and glands in
producing placental structures designed for both
efficient interchangeandbarrieris
one of the
greatest biological marvels.
Harland W. Mossman (1987)
‘Presented a t a symposium titled “Utero-placental-fetal Interactions” attheMidwestern
Section ASAS 27thAnnu. Mtg., Des
Moines, IA.
2We thank our collaborators ( C . L. Ferrell, Nutrition Unit, U.S.
Meat Anim. Res. Ctr., Clay Center, NE; S. P. Ford, Dept. of h i m .
Sci., Iowa State Univ., Ames; and S. D. Killilea, Dept. of Biochem.,
North Dakota State Univ., Fargo), technicians (J. E. Infeld, J. D.
Kirsch, K. C. Kraft, and D. A. Robinson) and graduate students(M.
L. Johnson, Y . Ma, and J. Zheng), all of whom have contributed t o
the studies described in this manuscript, and without whom this
work would not have been accomplished. This work has been
supported in part by grants from the National Institutes of Health
(XICHD 22559) and National Science Foundation (RII86-10675).
Journalarticle no. 2213 of theNorthDakota
Agric. Exp. Sta.,
Project 1782.
3T0 whom correspondenceshould
be addressed.
Received August 8, 1994.
Accepted February 16, 1995.
Mossman ( 1937), in his classic monograph, stated
that “the normal mammalian placenta is
an apposition or fusion of the fetal membranes to the uterine
mucosa for physiological exchange.” This definition
has three key aspects: 1) apposition or fusion indicates that the placenta involves intimate contact; 2 )
this intimate contact is between the fetal membranes
(chorioallantois) and the uterine mucosa (endometrium); and 3 ) physiological exchange istheprimary
role of such intimate contact between fetaland
maternal tissues. Indeed, all of the respiratory gases,
nutrients, and wastes that areexchanged between the
maternal and fetal systems are transported via the
placenta (Ramsey, 1982; Faber
and
Thornburg,
1983).Thus,the
importance of transplacental exchange in supplying the metabolic substrates required
for fetal growth isapparent,andhas
long been
recognized (Needham, 1934; Ramsey, 1982; Faber and
Thornburg, 1983; Morriss and Boyd, 1988). The
placenta also has additional functions such as production of hormones, which probably havea profound
influence on growth and development of the fetus and
utero-placenta, and perhaps even on their metabolism
(Conleyand Mason, 1990; Ogren andTalamantes,
1994; Solomon, 1994; Anthony, 1995).
1839
1840
REYNOLDS
Umbilical
Uterine
Artery (a)
(A) Artery
GRAVID UTERUS = Utero-placenta + fetus
1) GRAVID UTERINE UPTAKE
= ([A]
-
- [V]) x Uterine blood flow
2) FETAL UPTAKE= ([v] [a]) x umbilical blood flow
3) UTERO-PLACENTAL UPTAKE
= Gravid uterineuptake -fetal uptake
Figure 1. Schematic representation of the maternal,
utero-placental, and fetal compartments of the pregnant
female, and equations for calculating gravid uterine,
fetal, and utero-placental uptakes of substances based on
the Fick principle (seetext for further explanation).
Transplacental Exchange
Theimportance of placental function is probably
best exemplified by the close relationship between
fetal weight, placental size, and uterine and umbilical
blood flows in many mammalian species (Ibsen, 1928;
Warwick, 1928; Hammond, 1935; McKeown and Record, 1953; Alexander, 1964a; Oh et al., 1975; Wooton
et al., 1977; Christenson and Prior, 1978; McDonald et
al., 1979; Prior and Laster, 1979; Hard and Anderson,
1982; Caton et al.,1984; Ford et al., 1984; Reynolds et
al., 1984; Metcalfe et al., 1988; Ferrell, 1989; Ferrell
and Reynolds, 1992). Additionally, factors that affect
fetalgrowth,such
asmaternal genotype, increased
number of fetuses, maternal nutrient deprivation, or
environmental stress, typically have similar effects on
placental size (Walton and Hammond, 1938; Ebbs et
al., 1942; McKeown and Record, 1953; Eckstein et al.,
1955; Hunter, 1956; Joubertand Hammond, 1958;
Alexander,
1964a;
Alexander and Williams, 1971;
Turman et al., 1971; Rattray et al., 1974; Corah et al.,
1975; Sreenan and Beehan, 1976; Knight et al., 1977;
Thompson et al., 1982; Ferrell,1991a).Fetaland
placental weights also are reduced when the available
uterine surface area is reduced experimentally (Alexander, 1964b; Knight et al., 1977).
Schematically, the placentacan
be depicted as
being interposed between thematernalandfetal
compartments (Figure l). The term “utero-placenta”
evaluating
typically is used to indicate that, in
placental function in vivo,one cannot separatethe
uterine components that contribute to placental function (i.e., the endometrium) from those that do not
(i.e., the uterine serosa and myometrium). Nonethe-
PL N D REDMER
less, because the nonplacental components of the
uterus contribute little to gravid uterine metabolism
or transplacental exchange throughout most of gestation, the utero-placenta probably accuratelyreflects
placental function (Makowski et al.,1968a,b;Battagliaand
Meschia, 1981; Ferrell,1989).
As shown inFigure 1, to evaluate transplacental
of
exchange in vivo, one mustdeterminetherate
uterine blood flow on the maternal side as well as the
rate of umbilical bloodflow on the fetal side of the
utero-placenta.Then,
by usingthe
Fick principle
(Figure 1; Faber and Thornburg,1983; Ferrell, 19891,
uptake of any substance by the gravid uterus can be
calculated as follows:
gravid uterineuptake
([uterine
artery]
= uterine blood
flow
-
[uterine
vein]),
x
[l1
where [uterine artery] and [uterinevein] represent the
concentrations of the substance in the uterine artery
andvein, respectively. For example,gravid uterine
uptake of asubstanceinmilligrams/minute
would
equal uterine blood flow ( i n milliliters/minute) multiplied by the uterine arterial - uterine venous concentration difference in the substance (i.e., theextraction
of thesubstance per unit of blood, in milligrams/
milliliter). Likewise, fetal uptake can be calculated as
follows:
fetal uptake = umbilical blood
flow
x
([umbilical vein] - [umbilical artery]).
[2]
Utero-placental uptake can then be calculated as the
difference between graviduterineuptakeandfetal
uptake (Figure 1). Note that gravid uterine uptake
represents uptake by the total gravid uterus, which
consists of both the utero-placental and fetal compartments (Figure l).Additionally, whether the uptakes
by the gravid uterus,utero-placenta, or fetus are
positive, indicating consumption, or negative, indicating secretion, determine the direction of transplacental exchange, or net flux, of any substance (Figure2 j .
Studies of transplacental exchange have indicated, for
example, thatin
addition to being an organ of
transport,theutero-placenta
also is a metabolic
organ, producing such metabolites as lactate and urea;
this has been confirmed in several in vivo and in vitro
studies(Ferrellet
al., 1983, 1985; Reynolds etal.,
1985a; Morriss and Boyd, 1988; Battaglia,1992).
Relationships Among Fetal Growth,
Placental Growth, and
Placental Function
In the manymammalian species that have been
studied, weight of the fetusincreasesexponentially
throughoutgestation (Evansand Sack, 1973). The
1841
PLACENTAL FUNCTION AND ANGIOGENESIS
MATERNAL
UTERO
FETAL
30
A.
Uterlne C Fetal
B.
Uterlnec
Fetal
-0.5
Uterlne = Fetal
-1.O
S
(.W2-.M@l452l)t
2
25
.
8
Wt=.463e
4.5
Utenlne > Fetal
-
-&-20
-
0
8
0
8
8
8
R =.W,Pc.001
,’
Placentoma1
Wk1.757e
;
(.0616-.0001203t)t
8
2
8
R =.V,
Pc.001
80
*
0
8
c.
UterlneC Fetal
15
-
10
-
8
8
8
+0.5
8
0
0
8
D.
Uterlne C Fetal
0.5
Uterlne
-1.o
Fetal
I
Figure 2. Schematic representation of the direction of
transplacental exchange (net flux) of substances based
on the magnitude (uterine vs fetal) and direction (+
uptake vs - uptake) of uterine and fetal uptakes (see text
for further explanation), For illustrative purposes, arbitrary values are given.
following exponential model, where W = weight in
grams, WO= initial weight, b l = initial growth rate per
day, b2 = change in growth rate per day, and t = day of
gestation,has been used to describe fetal growth
(Koong et al., 1975; Reynolds et al., 1990):
W = W&
b l - b2 t)t.
Dl
Equation [3] indicates that the relative rate of fetal
growth ( t h e proportional increase per day), which is
represented by the exponent of e , decreases as
gestation advances. Thus, the model for fetal growth
in cattle (Figure 3 ) indicates an initial growth rate
( b 1) of 8.02% per day, which decreases by .014% per
day (b2 ) as gestation advances. This model fits the
actual relative rateof fetal growth extremely well ( R 2
= .99), and accurately predicts the sigmoidal pattern
of
of fetal growth. The model also agrees with the data
Koong et al. (1975) for sheep and Ferrell etal. (1976 1
for cattle, who reported a decrease in the relative rate
of fetalgrowth
as gestation advanced.
Despite the continual decrease in the “relative” rate
of fetal growth (percentage per day), the “absolute”
rate of fetalgrowth (kilograms per day) increases
exponentiallythroughoutgestation,because
of the
large increase in fetal weight as gestation advances
(Figure 3 ) . In other words, as gestation advances the
percentage increase per day becomes smaller, but the
-
100
8
0
150
200
250
DAY OF GESTATION
Figure 3. Regressions of fetal and placentoma1
weights (wt) on day of gestation in cows. Adapted from
Reynoldset al. (1990). Seetextfor explanation of the
regression model.
absolute increase is greater because of the larger fetal
mass. In addition, as shown in Figure 3, fetal weight
increases most dramaticallyduringthelasthalf
of
gestation, and this occurs in all mammals that have
been studied (Evans and Sack, 1973; Ferrelletal.,
1976).
In cattle, placental weight also increases exponentially throughout gestation, but the absolute rate
of
increase ismuch less than thatof fetal weight (Figure
3; Ferrell et al.,
1976;
Ferrell
and Ford, 1980;
Reynolds etal.,1990).Insheep,
placental weight
ceases to increase or even decreases after d 90 of
gestation (Barcroft, 1946; Wallace, 1948; Alexander,
1964a). A similar pattern of dramatic growth of the
last half
fetus but limited placental growth during the
of gestation has been documented for severalother
mammalian species (Ibsen, 1928; Warwick, 1928;
Hammond, 1935). Nevertheless, a positive correlation
between fetal and placental weights hasbeen reported
for many species (Ibsen, 1928; Warwick, 1928; Hammond, 1935; McKeown and Record, 1953; Alexander,
1964a).
Although weight provides an indication of the
pattern of placental growth,it isonly a gross measure.
For example, when weight of thecaruncularand
cotyledonary tissues (maternal and fetal components
1842
REYNOLDS AND REDMER
CARUNCULAR
3.5 32.5
COTYLEDONARY
l
-
M
\
i?
2 -
4
z 1.5
*
1-
0.5
-
0-
100
150
200
250
Day of Gestation
Figure 4. Concentration of DNA in caruncular and
cotyledonary tissues throughout gestation in cows.
Adapted from Reynolds et al. (1990).
of the placentomes, respectively) were evaluated
separately,theincreaseincaruncular
weight was
of cotyledonary weight
2.4-fold greaterthanthat
during the last two-thirds of gestation (Reynolds et
al., 1990). However, caruncular DNA concentration
remains
relatively
constant
from 100
d to
250,
whereas cotyledonary DNA content increases, indicating thatthe cellulardensity of the cotyledons increasesthroughoutgestation(Figure
4; Baserga,
1985; Reynolds et al., 1990).Because of this difference
in
their
patterns
of growth, the caruncles and
cotyledons have a similar increase(approximately
19-fold) in their total number of cells from d 100 to d
250, even though the absolute mass of the cotyledons
increases much more slowly than that of the caruncles
(Reynolds et al., 1990). Whethera similar differential
cotyledonary
pattern of growth of caruncularand
tissues occurs in other placentoma1 mammals(e.g.,
buffalo, deer,goats,sheep)has
not been reported.
However, the interplacentomal tissues of cattle have a
of growth; DNA concentration of
similarpattern
maternalintercarunculartissuesremainsconstant,
whereas that of fetalintercotyledonarytissues
increases threefold from d 100 t o 250 of gestation
(Reynolds et al., 1990).
Given itsfundamental role in providing for the
metabolic demands of thefetus,it
is clear that
placental function must keep pace with fetal growth;
that is, unless placentalfunction increases proportionately with fetal weight, the
metabolic demands of fetal
growth cannot be met (Metcalfe et al., 1988; Ferrell,
1989). Theobservation that placental growth does not
keep pace with fetal growth led Huggett and Hammond ( 1952) to suggest that “the size to which the
fetal
placenta
grows during
the
early
stages
of
pregnancy may determine, other things being equal,
the amount of nutrition that is at the disposal of the
fetus for growth during the later stagesof pregnancy.”
They seem t o have been suggesting that the placenta
grows beyond its needs early in gestation, in preparation for the tremendous metabolic demands of fetal
growth later in gestation. However, they also pointed
out thattheir proposal may not be entirely valid
because placental weight may not accurately reflect
placental function.
In fact, wenow
know thatalthough
placental
growth slows, placental transport capacity keeps pace
with fetal growth. For example, in sheep and cattle,
uterine bloodflow increases approximately three- to
fourfold from mid- t o late gestation (Figures 5 and 6;
Rosenfeld et al., 1974; Reynolds etal.,1986).
This
continualincrease in the rate of uterine blood flow
also seems to be the case for the other mammalian
species studied to date, including humans (Hard and
Anderson, 1982; Meschia, 1983; Ford et al., 1984;
Metcalfe et al., 1988). Additionally, umbilical blood
flow also increasesthroughoutgestation(Figure
6;
Reynolds et al., 19861, and umbilical blood flow per
kilogram of fetusremainsconstantthroughoutthe
last half of gestation, averaging .22 L.min-l.kg-l in
sheep and .l8 L.min-l.kg-lincattle(Rudolphand
Heymann, 1970; Reynolds andFerrell,1987).
Not
only do their rates increase throughout gestation, but
the proportion of the total uterine andumbilical blood
flows received by thecaruncularand
cotyledonary
tissues, respectively, increasethroughoutgestation
(Makowskiet al.,1968a,b; Rosenfeld etal., 1974;
Meschia, 1983).
Other placental functions such as placental transport of oxygen and water, bothof which are critical for
continued fetal growth (Barcroft, 1946; Faberand
Thornburg, 1983; Meschia, 19831, also keep pace with
fetal growth (Figures 7 and 8). Thus, as reported for
umbilical blood flow, oxygen uptake and water transport remain constant when expressed per unit of fetal
weight (Meschia, 1983; Reynolds et al., 1986; Reynolds andFerrell,1987).Incattle,fetal
oxygen
uptakeandwatertransport
per kilogram of fetus
average .22 mmoVmin and . l 2 Llmin, respectively,
from d 137 to 250 of gestation (Reynolds et al., 1986;
Reynolds and Ferrell, 1987). Similarly, fetal uptakeof
glucose keeps pace with therate
of fetalgrowth
(Reynolds etal., 1986). However, fetal uptake of some
substances, such as a-amino nitrogen, does not seem
to keep pace with the increase in fetal weight from
al., 1986; and
mid- t o lategestation(Reynoldset
Figure3),butthe
reason for this is not clear.
Placental
transport
capacity
could increase as
gestation advances because of an increase in the rate
of extraction of substances from uterine or umbilical
blood (i.e., by increasing the arterial-venous concentration difference [Barcroft, 1946; Faber and Thornburg, 1983; Meschia, 19831). Indeed,extraction
of
PLACENTAL
FUNCTION
.a
E
B
0
E
80
1.4
-
1.2
-
W
g
3
+Uterine
1-
-
0.4
o*20
*
0
.-e--Umbilical
Umb=.Olle
0.8
14 0.6
a
W
z
1843
AND ANGIOGENESIS
-
0
m
-
40
60
80
100
120
140
DAY OF GESTATION
CQ...---
Figure 5. Regression of uterine blood flow (UBF) on
day of gestation in ewes. From
Meschia
(1983).
I
140
oxygen per unit of uterine blood increases from mid- to
lategestationin
sheep andcattle(Meschia,
1983;
Reynolds et al., 1986). However, based on the Fick
principle as given inEquations [ l 3 and [21, transplacental exchange can increase notonly by increasing
the rateof extraction but also by increasing the rateof
blood flow. Based on numerous studies, it seems that
increased blood flow, rather than increased extraction,
is the primary mechanism of increased transplacental
exchange throughout gestation (Meschia, 1983; Reynolds et al., 1986; Metcalfe et al., 1988; Ferrell, 1989).
For example, althoughoxygen extraction by the gravid
uterus increases .4-fold, uterine bloodflow increases
approximately 3.4-fold from mid- to late gestation in
cattle (Table 1). Thus, increased uterine bloodflow
accounts for 71% of the five-fold increasein total
gravid uterine oxygen uptake (Figure7 1. Similarly, in
sheep
gravid
uterine
oxygen extraction
increases
approximately .4-foldfrom
mid- to lategestation,
whereasuterine bloodflow increasesapproximately
3.2-fold (Meschia,1983).In
addition, the 16-fold
increase in oxygen uptake of the bovine fetus from
mid- to late gestation (Figure 7) can be accounted for
by increased umbilical bloodflow (Reynolds et al.,
1986). The large increase in gravid uterine and fetal
uptakes of glucose, lactate, and a-aminonitrogen from
mid- t o late gestation in cows also seem to depend
primarily on the
large
increase in
uterine
and
umbilical blood flows (Figure S ) because their arterial-venousconcentration differences remainrelatively constant(Reynoldsetal.,1986).
I
160 220
200
180
I
I
I
240
260
I
DAY OF GESTATION
Figure 6. Regressions of uterine (Ut) and umbilical
(Umb) blood flows on day of gestation in cows. Based
on Reynolds and Ferrell (1987).
Based on these observations, adequate blood flow to
the placenta seems critical for normal fetal growth. In
further support of this concept, conditions associated
with reduced rates of fetal and placental growth (e.g.,
of fetuses,
maternal genotype, increasednumbers
maternalnutrient
deprivation,environmentalheat
stress) also are associatedwith
reduced rates of
placental blood flow and reduced fetal oxygen and
nutrient uptakes (Wootton et
al., 1977; Christenson
and Prior, 1978; Morriss et al., 1980; Ford et al., 1984;
Reynolds et al., 1985a,b; Ferrell, 1991a,b; Ferrell and
Reynolds, 1992). Thus, factors that influence placental vascular development and function will have a
tremendous impact on fetal growth and development
and,ultimately,
on neonatalsurvivalandgrowth
(Alexander, 1974; Huffman et al., 1985).
Patterns of Placental Vascular
Development
Based on the concept that chronic increases in blood
flow to any growing tissue depend on vascular growth,
Meschia (1983)statedthat“thelarge
increase of
REYNOLDS AND REDMER
12 -
+Uterine
10
-
Ut=.17!k
Clr=.0086e
2
616
R =.93, P<.Ool
R =sb,P<.odl
.-e-8 -
Umb=.016e m
R
=94.p<.m1
6 -
4 -
140
160
180
200
220
240
260
DAY OF GESTATION
Figure 7. Regressions of uterine (Ut) and umbilical
(Umb) oxygen uptakes onday of gestation in cows.
Adapted from Reynolds et al. (1986).
- 140 160 180 200
220
240
260
DAY OF GESTATION
blood flow to the uterus during pregnancy . . . results
primarily from the formation and growth of the
placental
vascular
bed. Thus,in
considering the
regulation of placental blood flow, a distinction should
be made between chronic regulatoryagents, which
modify the
magnitude
of uterine blood
flow
by
influencing the development of the placental circulation, and short-term regulators, which act by rapidly
changing thediameter of the placentalcirculatory
channels." In fact,tissuegrowthnormally
does not
occur in the absence of vascular growth (Hudlicka,
1984). For example, solid tumors will not grow beyond
approximately 1 mm3 unless they are able to recruit a
vascular
supply
(Folkman
and
Klagsbrun, 1987;
Klagsbrunand D'Amore, 1991). This dependence of
tissue growth on vascular development results from
the high metabolic demandsassociatedwithtissue
growthand the limitedability of respiratory gases,
nutrients, and metabolic wastes to diffuse through the
Figure 8. Regression of clearance (Clr) of water (D20)
across the placenta on day of gestation in cows. Adapted
from Reynolds and Ferrell (1987).
extracellular compartment (Hudlicka, 1984; Adair et
al.,1990).Thus,
growth and development of the
vascular bed are critical components of tissue growth,
including that of the utero-placental tissues, and the
importance of vascular development in placental
function has long been recognized (Hammond, 1927;
Hertig, 1935; Barcroft, 1946;Stegeman, 1974; Teaadale, 1976; Ramsey,
1982,
1989; Meschia, 1983;
Meegdes, 1988). However, other
than
descriptive
histology (Hertig, 1935; Barcroft andBarron, 1946;
Hutchinson, 1962; Kaufmann and Burton, 1994), only
a few quantitative
studies
of placental
vascular
growth have been reported.
Table 1. Uterine and umbilical blood flows per unit of placental tissue throughout gestation incowsa
Days of gestation
Blood flowb,
L.rnin-l.kg-l
137
180
226
250
Change
Uterine
Umbilical
5.99
.7 1
3.26
1.22
3.18
1.93
4.32
3.59
-.28
5.06
'Adapted from Reynolds et al. (1986, 1990).
bUterine and umbilical blood flows are expressed as
liters.rninute-'.kilogram-'
of caruncular or cotyledonary tissues, respecti\rely.
1845
PLACENTAL FUNCTION AND ANGIOGENESIS
During growth of mostorgans
or tissues,the
vascular bed and the other tissue
components grow
proportionately (i.e., vascular growth keeps pace with
growth of the tissues [(Hudlicka, 1984; Folkman and
Klagsbrun, 1987; Adair et al., 1990; Reynolds et al.,
1992a1). For
example,
innonpregnant
ewes, the
weight of the uterus is approximately 40% greater at
estrusthanduringthe
mid-lutealphase,whereas
density of the endometrial microvasculature remains
constant throughout the estrouscycle (Reynolds et al.,
1992b). Similarly, in ovariectomized ewes, treatment
withestradiol for 2dincreasesuterine
weight by
GO%, but endometrial microvascular density does not
change(Reynolds et al., 199213). Thus, in nonpregnant ewes, endometrialvascular
and nonvascular
growth are coordinated, because thedensity of the
microvessels does not change even when uterine
weightsvarysubstantially.
In contrast, we recently reported not only uterine
growth, but also a substantial increase(approximately
60%)
in
the
density of the endometrial
microvasculature, by d 24 aftermatingin
ewes
(Reynolds and Redmer, 1992). As mentioned already,
vascular density of tissues normally remains constant
and
is
proportional t o their metabolic demands
(Hudlicka, 1984; Adair et al., 1990). We hypothesized,
therefore, that density of the endometrial microvasculature increases during early pregnancy in response
to the metabolic demands of endometrial growth and
also to those of conceptus growth and development
(Reynolds and Redmer, 1992; Reynolds et al., 199213).
is
This increased endometrial microvascular density
associated with a three- to fivefold increase in the rate
of uterine blood flow from d 11 to 30 after mating in
ewes (Greissand Anderson, 1970; Reynolds et al.,
1984).
Vascular growth of endometrialtissues seems to
continuethroughoutgestationin
ewes. Stegeman
( 1974 reported that vascular density of caruncular
tissuesincreasessubstantially
from d 40 through
midgestation, and more slowly thereafter (Figure 9).
Vasculardensity
of thefetal
cotyledons, however,
remains relatively constant
until midgestation, then
increases dramatically thereafter (Figure 9; Barcroft
andBarron, 1946; Teasdale,1976).Thesedataare
consistent with the dramatic increase in uterine and
umbilical blood flows discussed already, and with data
indicating that umbilical bloodflow increases more
rapidly than uterine blood flow during the last half of
gestation (Rudolph and Heymann, 1970; Rosenfeld et
al., 1974; Reynolds andFerrell,1987).
By injecting a radiopaque dye intotheuterine
vasculature, Hutchinson ( 1962) observed continued
growth of the caruncularmicrovasculature throughout
gestation in cows. Whether caruncular vascular densheep,
has
not been
sity also increases, as in
determined. Likewise, whether cotyledonary microvascular density changes hasnot been evaluated through-
9
#
l
l
#
l
-+- Caruncular
.l5
l
I
6
- - 0- - Cotyledonary
I
l
l
l
l
I
I
I
l
l
‘10
{
I
8
l
l
l
.05
0
I
I
40
60
I
I
I
80 120100
I
140
DAY OF GESTATION
Figure 9. Microvascular density of caruncular and
cotyledonary tissues throughout gestation in ewes. From
Stegeman (1974).
out pregnancy in cows. However, the rateof blood flow
per unit of caruncular
tissue
remains
relatively
constant from mid- to late gestation in cows, whereas
bloodflow per unit of cotyledonary tissue increases
approximately fivefold (Table 1). Additionally, increased DNA concentration of bovine cotyledonary
tissuesthroughoutgestation(Figure
4 ) probably
reflects increasedcellulardensity,because
cell size
increases only slightly, and we have suggested that
this cotyledonary hyperplasia mayoccur due to growth
of microvessels (Reynolds et al., 1990). Thus incows,
as in sheep, density of the cotyledonary microvasculature seems to increase more rapidly than that of the
caruncularmicrovasculature,
which would partially
account for the more rapid increase in umbilical blood
flow compared with uterine blood flow during the last
half of gestation (Reynolds et al., 1986; Reynolds and
Ferrell,
1987).
Although growth of placental microvasculature is
important for placental growth and function, i t cannot
account completely for thesubstantialincreasein
placental blood flow that occurs during pregnancy. For
REYNOLDS AND REDMER
1846
example, in ewes, even though
caruncular
and
cotyledonary vascular
densities
increase
approximately .5- and sixfold, respectively, from mid- to late
gestation (Stegeman, 19741, uterineand
umbilical
3.5- and
blood
flows
increase
approximately
19-fold (RudolphandHeymann,
1970; Rosenfeld et
al., 1974). Similarly, it seems unlikely that growth of
placental microvasculature can account completely for
the 3.4- and 19-fold increase in the rates of uterine
and umbilical bloodflows
duringthelasthalf
of
gestationin
cows (Reynolds et al.,1986).Thus,
vascular growth and vasodilation are probably importantinensuringadequate
placental bloodflow
to
supportfetal growth (Reynoldsetal., 1992a;Ford,
1995).
Regulators of Placental
Vascular Development
Angiogenesis refers to the formation of new blood
an essential
vessels, or neovascularization, andis
component of growth and development of all tissues,
including the placenta (Hudlicka, 1984; Folkman and
Klagsbrun, 1987; Klagsbrun and D’Amore, 1991;
Reynolds et al., 1992a).The angiogenic process begins
withcapillaryproliferation
andculminatesinthe
formation of a new microcirculatory bed, composed of
arterioles,capillaries, and venules (Hudlicka, 1984;
FolkmanandKlagsbrun,
1987; Klagsbrunand D’Amore, 1991). The initial component of angiogenesis,
capillary
proliferation,
consists of at least
three
processes: 1) fragmentation of the basal laminaof the
existing vessel; 2 ) migration of endothelial cells ( t h e
primary cell type comprising capillaries) from the
existing vessel toward the angiogenic stimulus; and3 )
proliferation of endothelial cells (Hudlicka, 1984;
Klagsbrun and D’Amore, 1991). Neovascularization is
completed by formation of capillary
lumina
and
differentiation of the newly formed capillariesinto
arteriolesandvenules(Hudlicka,
1984; Klagsbrun
and D’Amore, 1991).
In most adult tissues, capillary growth occurs only
rarely,andthevascularendotheliumrepresents
an
extremely stable population of cells with a low mitotic
rate(Denekamp,
1984; Hudlicka, 1984; Klagsbrun
and D’Amore, 1991). Angiogenesis does occur in
adults during tissue repair, such as in the healing of
wounds or fractures (Hudlicka, 1984; Klagsbrun and
DAmore, 1991).In addition, angiogenesis occurs in
tissues with periodic growth and development, such as
those of the female reproductivesystem (Hudlicka,
1984; Klagsbrun and D’Amore, 1991; Reynolds et al.,
1992a; Reynolds et al., 1993).Angiogenesis in normal
adult tissues has been likened to processes such as
blood clotting, which must remain in a constant state
of readiness yet must be held in check for long periods
of time (Folkman and Klagsbrun, 1987). Angiogene-
sis, therefore, is thought to be regulated by angiogenic
and antiangiogenic factors (Hudlicka, 1984; Folkman
and Klagsbrun, 1987; Reynolds et al., 1992a).
Development of in vivo and in vitro assays within
the last two decades has made possible the isolation
and characterization of angiogenic and antiangiogenic
factors (Folkman and Klagsbrun, 1987; Reynolds et
al., 1992a).
The
in
vivo methods,
primarily
the
corneal pocket assay and the chicken chorioallantoic
membrane ( C A M ) assay, have been used to evaluate
the ability of a factor to influence neovascularization,
that is, to influence the entire process of angiogenesis
(Folkman
and
Klagsbrun,
1987).
Tissues from
tumors, corpus luteum, uterus, and placenta induce a
neovascular response in theCAM assay, whereas most
other adult or fetal tissues do not (Hudlicka, 1984;
Reynolds et al., 1992a).
In contrast with in vivo techniques, in vitro assays
evaluate the ability of a factor to influence one of the
individual components of the angiogenic process.
of substance
a
to
Theseassaystesttheability
influence the 1) production of proteases by endothelial
cells, 2 ) migration of endothelial cells, or 3 proliferation of endothelial cells (Folkmanand Klagsbrun,
1987; Klagsbrun and D’Amore, 1991). Factors identified with these in vitro bioassays are likely to have
similar effects in vivo, because thereisagreement
among in vivo andin vitro assays for angiogenic
factors (Folkman and Klagsbrun, 1987; Reynolds et
al., 1987; Redmer et al., 1988). Nevertheless, angiogenic activity of potential angiogenic factors must be
confirmed with one of the in vivo bioassays (Folkman
and Klagsbrun, 1987; Klagsbrun and DAmore, 1991).
Angiogenic activity of placentaltissues from human, bovine, and ovine sources has been evaluated by
using
in
vivo (CAM)
and
in
vitro (endothelial
protease production, migration, and
proliferation)
assays(Burgos,
1983; Gospodarowicz etal.,
1985;
Reynolds etal., 1987; Reynolds and Redmer, 1988;
Moscatelli et al., 1988; Millaway et al., 1989; Taylor et
al., 1992). In cows and ewes, these angiogenic factors
are produced primarily by maternal placental (endometrial) butnot fetal placental tissues (Reynolds et
al., 1987; Reynolds and Redmer, 1988; Figures 10 and
11).It
seems,therefore,
thatmaternal
placental
tissuesmaydirectplacentalvascularization.
If this
hypothesis is correct, factors that influence maternal
placental production of angiogenic factors could have a
significant effect on placental size, transport, and(or)
blood flow, thereby affecting fetal growth and development. Such factors include maternal genotype, multiple fetuses,inadequatematernalnutrition,andenvironmentalstress(Reynolds
et al., 1987; Ferrell,
1989).
Although angiogenic factorsseem tobe produced
primarily by the maternal placental tissues, this does
not exclude the possibility thatthefetalplacenta
participates in the regulation of placental vascularization. For example, endometrial vascularity is greater
1847
PLACENTAL FUNCTION AND ANGIOGENESIS
0CAR
COT
l
l
100
150
200
I SE
(n = 5 to 7/d)
I SE
(n = 4 to 61d)
250
DAY OF GESTATION
18
24
30
DAY OF GESTATION
Figure 10. Effects of media conditioned by bovine
caruncular (CAR) and cotyledonary (COT) tissues on
proliferation of endothelial cells. Controls (unconditioned media) represent 100%. Adapted from Reynolds
and Redmer
(1988).
Figure 11. Effects of media conditioned by ovine
caruncular (CAR) and cotyledonary (COT) tissues on
proliferation of endothelial cells. Controls (unconditioned media) represent 100%. Adapted from Millaway
et al. (1989) and Reynolds
et
al.
(1989).
in
the
pregnant
than
in
the
nonpregnant
state
(Hutchinson, 1962; Stegeman, 1974; Reynolds and
Redmer, 1992; Reynolds etal., 199213). Inaddition,
the presence of the conceptus induces utero-placental
growth and can induce phenotypic transformation of
the endometrial tissues. This latter ability is exemplified by thefrequentappearance
of “adventitious”
placentomes duringlate pregnancyin cows (Hammond, 1927; L. P. Reynolds and D. A. Redmer,
unpublished observations). These adventitiousplacentomes are smaller and more diffuse than the typical
placentomes but resemblethem
in otheraspects.
Thus, as stated by Hammond ( 19271, “it is apparent
that the power, not only of developing the dormant
also of initiatingthe
caruncles of theuterus,but
formation of new adventitious caruncular growth rests
with thefetal
membranes.”
Throughout most of gestation, the fetal placental
tissues of ewes and cows produce factor(s) that inhibit
endothelial cell migration and proliferation (Reynolds
and Redmer, 1988; Millaway et al., 1989). We suggest
that the target of these fetal placental antiangiogenic
factors is the maternal placental (uterine) vasculature, wheretheymay
function tolimitvascular
development. This proposal seems reasonable because
as the
angiogenesis innormal
adulttissues,such
uterus, must be held in check to prevent development
of a pathological condition resulting from rampant
capillary
growth
(FolkmanandKlagsbrun,
1987;
Klagsbrun and D’Amore, 1991).
In
addition, the
proposal that fetalantiangiogenicfactorsmaylimit
maternal placental vascular development is consistent
withthedataindicatingthatthefetal
genome
regulates placental size until late in gestation (Ferrell, 1991a). The presence of antiangiogenic factors in
fetal placental tissues would not be expected to have
an adverse effecton
fetalplacental
development,
because fetal placental vascular growth is a developmental process, sometimes
termed
vasculogenesis,
which may occur independently of angiogenic factors
(Hertig, 1935; Patten, 1964; Ramsey, 1982; Hudlicka,
1984). During a brief period late in gestation (approximately d 120 after mating), however, the ovine fetal
placenta produces an endothelial mitogen (Figure 11;
Millaway et al., 1989; Zheng et al., 19951, consistent
of fetal,but not
with theincreaseinthenumber
maternal, placental endothelial cells during this same
period (Stegeman, 1974; Teasdale, 1976).
Ovine endometrial
tissues
produce endothelial
mitogen(s) between
12
d
and 40 after
mating
(Millaway et al., 1989; Reynolds et al., 1992a). The
majority of this endothelial mitogen binds to heparinaffinity columns and has at least two peaks of activity
a saltgradient(Reynoldsetal.,
onelutionwith
1992a,b). This is significant
because previously identified fibroblast growth factors ( FGF), which constitute
a family of closely relatedproteins,haveastrong
af‘finity for heparin and are potent angiogenic factors
(Folkman and Klagsbrun, 1987; Burgess and Maciag,
1989). The prototypes of this family are FGF-1 and
FGF-2, also known as acidic and basic fibroblast
growthfactors,
respectively (Burgessand
Maciag,
1989).
The major peak of endometrial mitogenic activity,
which we have designated H3, elutes at approximately
1.9 M NaC1, which corresponds with the elution profile
1848
REYNOLDS AND REDMER
of FGF-2 (Burgess and Maciag, 1989). However, our
work indicates thatH3
is distinct from FGF-2
(Reynolds et al., 1992a,b). Forexample, FGF-2 is
mitogenic for BALB/3T3 cells, but H3 is not (Reynolds
et al., 199213). When subjected to ultrafiltration or to
SDS-PAGE, H3 seems to be greaterthan 70 kDa;
50 kDa (Burgessand Maciag,
FGF-2 islessthan
1989; Reynolds et al., 1992b).Mitogenic activity of H3
wasincreased
150% by addition of 50 pg/mL of
heparin,whereas mitogenic activity of FGF-2 was
unaffected by heparin(Burgessand
Maciag, 1989;
Reynolds et al., 1992a,b). In addition, FGF-2 was not
detected in ovine endometrial-conditioned media with
immunoblot or immunoneutralization procedures,
even though both procedures readily detected FGF-2
in luteal-conditionedmedia(Grazul-Bilska
etal.,
1992, 1993; Reynolds et al.,1992b).
Thus, we suggested that H3 may represent a novel
heparin-binding endothelial mitogen (Reynolds et al.,
1992a, 1993). Additionally, H3 may represent a large
molecular weight form of FGF-2, because multiple
forms of FGF-2have
been isolated from human
placenta
(Moscatelli
et al., 1988),and
we have
detected FGF-2 in ovine endometrial tissues by using
immunohistochemistry ( L . P. Reynolds and D. A.
Redmer,unpublishedobservations).
This suggestion
seems
reasonable
because
the presence of high
molecular weight,immunoreactiveFGF-2
inserum
has been reported for several species (Baird et al.,
1986). Although FGF-1and FGF-2 are synthesized
without a signal peptide and, therefore, do not seem to
be secretedproteins,theyhave
been found inthe
extracellular matrix ina variety of tissues (Vlodavsky
et al., 1990; Grazul-Bilska et al., 1992; Zheng et al.,
1993) andalso in the circulation. Thus, itseems likely
thatH3 produced by the ovine endometrium is a
secreted form of FGF.
Alternatively, H3 may belong t o another family of
heparin-binding angiogenic factors, known as vascular
endothelialgrowthfactors
(VEGF). The VEGF are
dimericproteins of approximately45kDa,
andare
specific mitogenic andmigration-stimulating factors
for endothelial cells (Ferrara et al., 1992). Additionally, VEGF seem to be presentinplacentaltissues
(Maglione et al., 1991; Sharkey et al., 1993). Interestingly, VEGF seems to be produced by sheepfetal
placental, but not maternalplacental,tissues
at
approximately d 120of gestation (Ebaugh etal., 1994;
Zheng et al., 19951, which is when the cotyledons are
producing angiogenic activity (Millaway et al., 1989)
and exhibitingrapidmicrovasculargrowth
(Stegeman, 1974; Teasdale, 1976). However, although
VEGF stimulates proliferation of endothelial cells, its
primary action seems to be stimulation of endothelial
cell migration (Plouet and Bayard, 1994). In contrast,
H3 seems to be produced by the maternal placenta,
is a potentenprimarily inearlygestation,and
dothelial mitogen. In addition, based on SDS-PAGE,
-
1
.
.1
H3 is not dimeric and is larger than known VEGF
(Ferrara et al., 1992; Reynolds et al., 1993). The H3
also elutes from heparin-affinity columns at a greater
salt concentration than VEGF (Ferrara et al., 1992;
Reynolds et al., 1992a). Thus, H3does not seem to be
a VEGF, but it could represent a novel member of the
VEGF family.
Implications
The
placenta
transports
respiratory
gases,
nutrients, and wastes between the maternal and fetal
systems, but itgrows primarily during the first half of
gestation.Placentalvasculargrowth,
however, continues;indeed,placentalvasculardensityincreases
throughoutgestation.Uterine
and umbilical blood
flows thereby increase throughout gestation, resulting
in increasedplacental transport capacity to support
fetal growth and
metabolism.
Angiogenic factors,
which probably coordinate growth of placentalvasculature, are produced by primarily maternal placentaltissues.
Theseplacental
angiogenic factors are
heparin binding and may be related to the fibroblast
growth factor family.
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