Medical Hypotheses (2004) 62, 511–519
http://intl.elsevierhealth.com/journals/mehy
The dynamic placenta: I. Hypothetical model of a
placental mechanism matching local fetal blood
flow to local intervillus oxygen delivery
D. Talberta, N.J. Sebireb,*
a
Institute of Reproduction and Developmental Biology, ICSM,
Hammersmith Hospital, Du Cane Road, London, UK
b
Department of Histopathology, Camelia Botnar Laboratories, Great Ormond Street Hospital,
Great Ormond Street, London WC1N 3JH, UK
Received 15 May 2003; accepted 16 October 2003
Summary The placenta can be severely infarcted and yet return well oxygenated blood in spite of the potential shunt
paths produced. Optimisation of oxygen transport by some form of local flow matching has been suggested, either via a
direct action of hypoxia on subchorial vessels, or indirectly by syncytiotrophoblastic metabolic products. Using casts of
cotyledonal vessels and software modelling, a mechanism of hypoxic fetoplacental vasoconstriction could be
demonstrated. A simple previously described passive placental model was extended to include hypoxic sensitive
arteries and dependence of syncytio-trophoblastic metabolism on intervillus (maternal) blood oxygen content. Such a
mechanism of placental flow matching could maintain fetal pO2 by reducing flow through inadequately oxygenated
cotyledons, therefore optimising pO2 at the expense of flow. A further modification stabilising fetal water transfer was
required to avoid changes in intervillus oxygen delivery producing changes in fetal water content via placental capillary
pressure alterations. Intervillus/villus flow matching is likely in the human placenta and this study suggests probable
biologically plausible mechanisms for such a phenomenon.
c 2004 Elsevier Ltd. All rights reserved.
Introduction
This study aims to investigate the well known
paradox that placental intervillus flow may be locally severely restricted, yet although umbilical
*
Corresponding author. Tel.: +44-20-7829-8663; fax: +44-207829-7875.
E-mail address: SebirN@gosh.nhs.uk (N.J. Sebire).
vein flow may be reduced, the blood returning to
the fetus remains well oxygenated in spite of the
shunt paths that should result. One possible explanation is that oxygen transport is optimised by
some form of local flow matching in the placenta
analogous to V/Q matching in the lung [1,2]. We
have proposed the term U/Q flow matching for any
such mechanism, to express the analogy with the
lung [3]. Restriction of blood flow through poorly
ventilated regions of the lung avoids “shunt” paths
which would be produced by areas of impaired
ventilation. Similar shunts would occur in the pla-
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2003.10.025
512
centa if utero-placental flow is locally inadequate.
Sensing of maternal blood O2 availability could be
direct, such as an effect on vascular smooth muscle, or indirect, such as production of vasoactive
metabolic products produced by trophoblast that
depend on oxygen from the maternal circulation
for their control, such as nitric oxide [4]. Endothelial nitric oxide synthase (eNOS) in the human
placenta is found in the syncytium in normal and
pre-eclamptic or IUGR pregnancies. In normal
pregnancies eNOS immunostaining is absent from
within the vessels of terminal villi and weak in stem
villous vessels but prominent at both sites in the
IUGR and pre-eclamptic groups [4]. It was suggested that NO may therefore have a flow regulatory role. Initially, it was believed that the half life
of NO in blood was less than 2 ms requiring any
regulatory mechanism to be very local. More recently, has been reported that breathing NO produces effects beyond the pulmonary vasculature
[5], and that infusion of NO solutions into the
brachial arteries of human volunteers induced dilation of the ipsilateral radial artery (ultrasonically
visualised at the wrist) and increased forearm
blood flow in the same and contralateral arm [6]. It
appears that in vivo, in the absence of RBCs such as
occurs near vessel walls, NO may have a half life in
plasma in the range of seconds to minutes. Additionally nitrosothiols in the plasma appear to
temporarily bind NO releasing it at remote sites.
This renders the above [4] hypothesis a valid
possible control mechanism around which to build
a theoretical model of utero-intravillus flow
matching.
An alternative explanation comes from Hampl
et al. [7], in which hypoxia was found to have a
direct vasoconstricting effect on small stem villous
vessels but not larger chorionic vessels. In the
human doubly perfused placental cotyledon, hypoxia produced a reversible increase in flow resistance by about 25% (Hypoxic Fetoplacental
vasoconstriction; HFPV), although the chorionic
vessels respond by dilating. They describe this as
Using patch-clamp techniques they also demonstrate that large, rapid and reversible changes in
membrane currents (110 to 40 pA/pF at 70 mV
membrane potential) occur with hypoxia on small
villous arteries and that small villus arteries have a
greater contribution of voltage dependent K+
channels than the large er chorionic vessels. They
also found that NO synthase inhibition by L-NAME
caused vasoconstriction during normoxia but the
the hypoxic vasoconstriction was unaltered and
suggested that NO is important in control of basal
vascular tone not the hypoxic response. In the
following hypothesis, we consider both mecha-
Talbert, Sebire
nisms and show that from a modelling point of view
they are equivalent.
Relevant aspects of placental cotyledonal
structure
Fig. 1 comprises stereo photographs of plastic casts
of the lumens of vessels associated with a group
of placental cotyledons, and Fig. 2 is a diagram
linking the features for an individual cotyledon.
Abbreviations in capital letters in the following
text refer to corresponding features in Fig. 2 (see
Legend).
Fig. 1(a) shows a cast of the lumens of a group of
six cotyledons of the type on which the computer
model was based. There would typically be 10–15
such groups in a complete placenta. The arterial
tree was injected with an acrylic plastic [8] until
it emerged from the vein. The vein was then
retrofilled with blue dyed plastic as far as the
cotyledonal stem veins. When hardened, all the
surrounding tissue was dissolved away leaving casts
of the lumens of the vessels. Each cotyledon is
about the same diameter as a UK 10p coin. The
group is supplied by a single chorionic artery (CHA)
and vein (blue; CHV), which lay on the upper (fetal)
side of the chorionic plate. The larger artery lumen
is about 3 mm diameter and the smaller branches
about 1 mm diameter. Where artery and vein meet
they appear to pass through the plate in very close
proximity, Fig. 1(b). The artery is in the form of a
helix, in close proximity to the vein. The gap seen
in Fig. 1(b) between the lower surface of the supplying chorionic artery and vein and the upper
surface of the cotyledons (5 mm) suggests that
the chorionic plate was about 3 mm thick in this
specimen. On emerging below the chorionic plate
these arteries and veins branch again to supply the
various fetal cotyledons. Occasionally, the blue
plastic penetrated a villous stem vein, Fig. 1(c)
(black arrow) where the corresponding stem artery
can be seen alongside, (STA, STV) in Fig. 2. In this
caste, stem arteries and veins were typically about
400 lm diameter. Among the mass of smaller vessels, pairs were sometimes seen (Fig. 1(c), white
arrow), typically of vessels about 100 lm diameter
separated by about 100 lm, which are thought to
have run through intermediate villi branches.
(Fig. 2, IV). It has not been possible to positively
identify the lumens of terminal villi (Fig. 2, TV)
amongst the complex network of other vessels. The
plastic may not have penetrated them or their
casts been too brittle to survive processing.
Fig. 1(d) shows the underside of a cotyledon and
a maternal spiral artery (SPA) entering the centre
The dynamic placenta
Figure 1 Placental Lobular vascular structure: plastic
casts of lumen configuration. These casts were obtained
by filling the region via a chorionic artery, and then,
before it had hardened, retro-filling with blue pigmented
plastic via the corresponding chorionic vein. When
hardened all tissue is dissolved away to leave casts of the
LUMENS, not the vessels themselves. The illustrations
form stereoscopic pairs for “Free Field” viewing which
does not require any apparatus. The picture for the left
eye is on the right and for the right eye is on the left. To
view the pairs the eyes are intentionally crossed and
relaxed until three pictures are seen, the centre one
appearing in 3-D. If the centre one appears as two images
slightly vertically displaced they can be brought level by
tilting the head. (a) General view of lobule. Five cotyledons remain, there is some suggestion that two further
cotyledons were originally present nearer the observer.
The supplying artery and vein approach from differing
directions. (b) Edge on view of the trans-chorionic plate
region. The artery and vein lumen shown are about 3 mm
diameter at this point. Although the artery appears to
spiral round the vein this has not been observed. It has a
helical configuration and lies very close to the vein as can
be seen by the narrow gap between the two lumens. The
gap between the underside of the chorionic vessel lumens and the top of the cotyledons is about 5 mm suggesting that the chorionic plate was about 3 mm thick in
this example. (c) Cotyledonal vessels. Only occasionally
did the blue material penetrate as far villous stem veins
(e.g., thick arrow). Stem artery lumens are about 400 lm
in this sample. Smaller artery and vein pairs, typically
about 100 lm diameter spaced about 100 lm apart (thin
arrow), should probably be classed as Intermediate vessels. They run parallel for many times their separating
difference. This is where vein to artery diffusion is represented as taking place in the software model. (d) View
from decidual aspect showing part of a spiral artery (red)
entering into the core region of a cotyledon.
513
Figure 2 This figure illustrates the physiological features represented in the software model shown in Fig. 3.
Fetal blood arrives at the cotyledonal site through a
branch of a chorionic artery CHA. It passes down through
the chorionic plate (CP) into a villous stem artery (STA)
and enters intermediate villi. The intermediate carry
many terminal villi in which most of the diffusional and
active exchange, synthesis, etc., is thought to take place.
Terminal villi are supplied from arteries running down the
intermediate villi (inset panel, IVA) oxygen taken up, and
nitric oxide (NO) added in proportion to local maternal
oxygen delivery. The blood then passes back up through
the intermediate villi veins (IVV) where the NO diffuses
out into the villus interstitium, and into the vascular
smooth muscle of the IVA walls. For mathematical simplicity the intermediate villi are grouped into three
classes, core, middle and outer layers corresponding to
“arterial”, “capillary”, and “venous” classifications suggested by Burton et al. [18]. Maternal blood enters from
the spiral artery (SPA) into the core of the cotyledon
which thus contains blood at the highest hydrostatic
pressure and oxygen content. It then flows between the
terminal villi of the three layers losing pressure and oxygen as it goes. On exiting it passes between neighbouring
cotyledons to the uterine veins (UTV).
of a fetal cotyledon from the underside. The surface of each cotyledon visible in Fig. 1(a) is the
outer layer of villi through which this maternal
blood escapes, to return between the cotyledons to
the utero-placental lake and uterine veins (Fig. 2,
ITV).
Mechanisms available for placental
autoregulation to match local fetal blood
flow to intervillus blood oxygen availability
Direct hypoxic fetoplacental vasoconstriction
(HFPV) is relatively straight-forward. In terminal
villi oxygen will be diffusing directly through the
interstitium into any vascular smooth muscle cells
514
it encounters to induce relaxation. It will also be
carried back through the venules into the stem
veins where the close proximity to stem arteries
will allow vasodilation as well. A fall in maternal
oxygenation will reduce this dilatory effect and
the vessels will contract. Indirect action is more
complex since for NO to have a regulatory role,
there has to be evidence that it represents some
aspect of maternal blood oxygenation and flow
rate, and that a mechanism may exist by which
it can then alter local blood flow. Syncytial metabolism depends on maternal blood oxygen status, indeed terminal villi remain viable after fetal
demise [9] provided spiral artery flow is intact.
So any metabolic products produced primarily reflect the adequacy of intervillus blood, rather than
fetal blood. Furthermore, the normal absence of
endothelial NO production capability in terminal
villi [4] means that such a signal is not masked by
endothelial production in the collecting veins up
until at least the villous stem veins. This makes it
an ideal signal with which to control matching of
intravillus fetal blood flow. It is then necessary to
consider how and where NO diffusing out of these
veins could enter the artery and/or arteriolar walls
and cause the smooth muscle to relax. From
Fig. 1(a) it is clear that there is no possible diffusive interaction above the chorionic plate because
chorionic artery and vein approach from different
directions. However, when they pass through the
chorionic plate, Fig. 1(b) they are in close proximity. Bearing in mind that these casts are of the
lumens of vessels, such close proximity suggests
that in vivo artery and vein must have been in intimate contact. Moreover, the artery at this point
often appears to be unnecessarily long, having
coiled into a helix, alongside, but not encircling,
the vein. Transfer could occur here. The blue veinfilling plastic was generally only advanced as far
the cotyledonal collecting veins, leaving both stem
arteries and veins in clear plastic, but where stem
veins have been coloured (thick arrow, Fig. 1(c)) it
is clear that they also run very close within the
stem villi. Similarly, where intermediate villus
vessels can be recognised their 100 lm separation
would certainly facilitate diffusion. If the active
vasodilator is NO, as Myatt et al. [4] suggested, an
NO half life of a few seconds would be sufficient to
make these the primary sites for vein to artery
diffusion. Intermediate villus vessels would thus
normally be held partially dilated by the NO surrounding them. If syncytial metabolism was reduced, NO concentration would drop and the
arteries and arterioles would contract towards
their natural diameter, reducing shunt flow. So the
basic concept of NO regulation of flow is compati-
Talbert, Sebire
ble with known placental microstructure and
function and would affect the same vessels as direct HFPV.
Consequential disturbance of
feto-maternal water balance
A complication encountered while constructing the
model was that reduction of villus capillary blood
flow inevitably reduces villus capillary lumen
pressure, causing water to enter the fetal blood
from the surrounding maternal blood. In somatic
tissues water leaves the arteriolar end of capillaries and returns at the venule end. Any imbalance of
these transmural flows alters the local interstitial
pressure. The new resulting pressure changes until
the outward and inward transmural transfers balance. There is then only a minimal net movement
[10]. In the case of chorionic villi, the surrounding
pressures are the hydrostatic and osmotic pressures of the maternal intervillus blood which are
unaffected by transfer to or from fetal blood because the maternal blood is continually being replaced by intervillus flow. Another mechanism is
required. Myogenic vasoconstrictive action regulates inlet pressure to most somatic capillary beds
and was considered. However, myogenic arteries
and arterioles, can only respond to upstream
pressure, (Starling effect; [11]) and would not be
able to adjust down stream capillary pressures to
control water transfer.
Further details are provided in the accompanying manuscript [12]; an outline is given here. Since
there are no neural mechanisms within the placenta itself to perform integration of water transfer one has to look to the fetus which is well
equipped to monitor changes in blood volume
through it’s venous and atrial stretch receptors.
Fetal control of placental vessels has been assumed
impossible because there are no neural connections between fetus and placenta, and hormonal
signalling would interfere with the fetus’ own internal regulatory actions. However sub-chorial arteries and veins (tissues of extra-embryonic origin;
[13]) differ from fetal body tissues in their response to some vasoactive substances [14,15]. It is
thus theoretically possible for the fetus to modify
subchorial venous resistances and hence venule
and capillary pressure either with a previously unrecognised circulating placental venous constrictive agent, or by the placenta mounting a different
response to a known vasoactive substance. It is not
possible in our model to distinguish between these
mechanisms, but the lamb model of Anderson and
Faber [16], in which angiotensin-1 paradoxically
The dynamic placenta
produced extreme polyhydramnios would fit if the
placenta expressed peptases converting angiotensin-I and angiotensin-II to angiotensin [1–7], a vasodilator. Stem villous veins have unusually well
developed VSM with which to respond [13]. Providing the fetal model with a fictitious hormone to
allow it to defend it’s water content by adjusting
villous capillary hydrostatic pressure by modifying
placental venous resistance, stabilised feto-maternal water transfer and allowed flow matching
studies to proceed. This fetal water volume defence system was active throughout the period in
which this flow matching study was proceeding.
Summarising, both the direct HFPV and indirect
NO mechanisms appear possible, produce similar
results, act at similar sites, and cannot be distinguished in the model. However, both require the
fetus to control mean villous capillary pressure
across the whole placenta to match the consequential intravillus pressure changes. Much of the
data required to investigate these coupled hypotheses is ethically impossible to obtain from the
515
human hemochorial placenta in vivo. The investigative technique used was to link a model of the
fetus (FETAL CHARLOTTE) previously described
[17] with a new model of the placenta, and introduce these recent concepts that would make the
placenta an active device.
Methods
Vascular network pattern
A schematic is shown in Fig. 3(a). To allow interaction of regions of the placenta with differing
maternal perfusion to be studied, the placental
model is divided into three sectors. Fetal blood
from the umbilical artery (Rumba) placental insertion enters each sector via a chorionic artery,
Chora[n], Fig. 3(a), where n identifies the sector
being supplied. Each sector has three villous trees
(cotyledons). Each cotyledon has a stem artery
Figure 3 (a) Schematic diagram of the complete placental model. Flow resistance components: Rumba ¼ umbilical
artery: Rchora ¼ chorionic artery, Rstma ¼ stem artery: Rinta ¼ Intermediate villus arteriole supplying terminal villi:
Rtvcap ¼ Terminal villus capillary: Rintv ¼ Intermediate villus vein: Rstmv ¼ stem vein: Rchorv ¼ Chorionic vein:
Rumbv ¼ Umbilical vein: (b) The matching mechanism in each cotyledonal layer. Maternal blood flows past (thick
arrows) terminal villi whose syncytium releases NO into the interstitium and hence capillaries of terminal villi in
proportion to pO2 within the syncytium. The NO is carried into the intermediate villi veins where it diffuses into the
smooth muscle of the artery walls (b) (curved arrow) and relaxes then to an extent proportional to intervillous oxygen
content and flow. (c) Maternal blood flow equivalent circuit. Starting at the pressure in the uterine arcuate arteries
maternal blood flows towards the uterine lumen through the radial (Rrada) and spiral (Rspira) arteries, through the
flow resistance of the three layers of the intervillous space, and back through the uterine venous network (Rutv) to the
maternal vena cava Pmivc. In the experiment illustrated in this report only spiral artery resistances were altered.
516
(Rstma) and stem vein (Rstmv). Each stem artery
supplies three intermediate villous arteries (Rinta)
representing (onion like) core, middle, and outer
regions of each cotyledon. These intermediate villi
carry terminal villi with capillaries (Grouped together and represented by Rtvcap), which are the
fetal side of the exchange apparatus. There are
thus 27 exchange sites per sector, 81 in the complete placental model. This may appear more
complex than necessary, but was done to facilitate
extension if unforeseen interrelationships were
revealed in the course of the research. Each cotyledon is associated with a spiral artery.
Feto-maternal gas exchange
Gas exchange is modelled as being flow limited,
i.e., it is assumed that the time that the fetal and
maternal bloods are in close proximity is sufficient
for equalisation of their oxygen partial pressures.
The amount of oxygen brought to each terminal
villus by the maternal blood in one fetal heart beat
interval is thus local intervillus flow in one fetal
heart beat interval, multiplied by it’s molar concentration of oxygen (bound and dissolved). On the
fetal side, the amount of oxygen brought to the
exchange site is luminal flow in this intermediate
villus, multiplied by the fetal descending aorta
oxygen content. The amount of oxygen gained by
the fetal blood equals that lost by the maternal
blood, and the pO2 of maternal blood entering the
next layer of villous branches is reduced accordingly.
Regulation of terminal villous flow
The regulatory sites for each layer of each cotyledon are the arteries and/or arterioles in its small
villus arteries, (Rinta, Fig. 3(b)). In the model,
these arterioles are allowed a 2:1 lumen diameter
ratio giving a 16:1 resistance ratio. When the
model is started NO is minimal and resistance is
maximum. Physiologically (in vivo) the minimum
diameter of arteries is limited by physical factors,
wall thickness, compressibility, etc., which are not
affected by NO. The maximum lumen diameter is
determined by physical restraints related to vessel
growth, collagen, elastin, basement membranes,
etc., again not directly related to VSM sensitivity to
NO. The fully relaxed (minimum resistance) value
occurs when the metabolic product producing relaxation reaches or exceeds a nominal value. Between these two extremes the current diameter
depends on the concentration of NO in the interstitium surrounding the vessels and the sensitivity
Talbert, Sebire
of the VSM to it. In the model, threshold sensitivity
and incremental sensitivity can be adjusted independently. As oxygen is extracted from maternal
blood NO increases, and as it passes a threshold
concentration villous arteriole resistance starts to
reduce and fetal blood flow increase.
Utero-placental circuit
Maternal “blood” (Fig. 3(c)) flows from the arcuate
arteries, through the radial (Rrada) and spiral arteries (Rspira), into the core of it’s associated
cotyledon. Ruivl,2,3 represent the intervillous flow
resistance of the arterial, capillary and venous
regions of each cotyledon as defined by Burton
et al. [18] Each spiral artery resistance can be
varied independently. Together with the radial artery (Rrada), flow resistance between cotyledons
(Rlake), and uterine vein resistances (Rutv) these
form a pressure divider chain from which the current intervillous pressures are calculated.
Monitoring display
Fig. 4(a) and (b) are screen dumps of a monitoring
display, generated while the model is running, used
to follow details of flows, pressures, oxygen status,
etc., in cotyledons within the sector selected.
There are two blood “circuits”, maternal and fetal.
The fetal blood flow and pressure is supplied to the
umbilical arteries from the descending aorta of the
FETAL CHARLOTTE model [17], whose umbilical
vein returns blood to it’s umbilical sinus. Each
chorionic artery supplies three stem arteries
Stma[n], where n identifies individual cotyledons in
that sector. Each set of three curved structures
represents (from left to right) the core, middle,
and outer regions of the cotyledonary villus structures, through which the maternal blood, represented by the horizontal bar passes. The terminal
villi layers are coloured to represent their oxygen
content to the colour code indicated in the block
on the left. The colour of the upper part indicates
the oxygenation of the fetal blood flowing in (from
the fetal abdominal aorta) and the lower section
that of fetal blood flowing out of that terminal
villus. The small blue panels indicate flow through
each intermediate villus layer in ml/min, and the
red panel immediately below, it’s oxygen content.
Oxygenated fetal blood from all three intermediate
villous layers then drains into the stem veins,
(Fig. 4, Stmv). Here it mixes to produce a mean
oxygenation and total cotyledonary flow, and flows
onward into the chorionic veins Chorv where further mixing occurs.
The dynamic placenta
517
The zig-zag, structures represent three of the
nine independently adjustable spiral arteries. In
Fig. 4(a) and (b) the horizontal bar lying behind
the curved villi represents the intervillus space
through which the maternal blood travels. The
spiral arteries deliver blood into the core space of
each cotyledon, (to the left of the curved villi) at
the hydraulic pressure over-printed. It then
moves (left to right in the figure) through each
layer of the terminal villi until it reaches the lake
region, where the mean lake pressure is overprinted, and out through the uterine collecting
veins. As oxygen is removed from the maternal
blood passing through the layers of intermediate
villi it’s colour (seen through the narrow gaps
between layers) is changed to the same code as
in the fetal circuit.
Results
Figure 4 Part of screen dumps of a run time display,
set to display sector 1: (a) U/Q matching enabled (ACTIVE); (b) U/Q matching disabled (PASSIVE). Each set of
three curved structures represent the core, middle, and
outer regions of the cotyledonary villous structures,
through which the maternal blood, represented by a
horizontal bar “behind” the curved elements passes.
These are the terminal villi of the model where fetomaternal gas exchange takes place. The curved terminal
villi layers are colour coded to represent blood oxygen
content to the bands indicated in the block on the left.
The upper part indicates oxygenation of the inflowing
blood (fetal abdominal aorta) and the lower section that
of fetal blood flowing out of that terminal villus. The
numbers in blue mini-panels indicate instantaneous flow
in ml/min. The numbers in red panels show the oxygen
content of the blood in the vessel concerned. (c) Intervillus Blood Oxygen Content. Each yellow panel is a
plot of the oxygen content of maternal blood as it travels
from a cotyledonal core to the lake region through the
three layers of terminal villi. The upper row were plotted
with U/Q matching active (DYNAMIC) mode and the lower
with U/Q matching inactivated (PASSIVE) mode. In each
case blood arrives at 9.5 mM. When spiral artery resistance is increased (resistance 2, 6) O2 extraction is
greater in passive mode, e.g., for 6 maternal blood
extraction is (9.5)7.4) ¼ 2.1 in ACTIVE mode but
(9.5)6.8) ¼ 2.7 mM in PASSIVE mode.
Placental behaviour with dynamic flow matching,
(Fig. 4(a); Dynamic Mode) was compared with that
when matching was disabled (Fig. 4(b); Passive
Mode), in particular the effects on umbilical venous
return flow and oxygen content and the features
causing them. Fig. 4 illustrates one such experiment
in which partial spiral artery occlusions were superimposed on a degree of maternal anaemia. One
spiral artery in each sector was left at nominal resistance (Fig. 4(a), left), one raised to twice normal
(centre) and one to six times normal (right). Since
all three sectors were set identically this display
represents what was happening in the placenta as a
whole. With the placenta set to dynamic mode
maternal haemoglobin was gradually reduced until
significant vascular constriction occurred in the
cotyledon with the most severely restricted (6
resistance) spiral artery in each sector, (Fig. 4(a),
right hand cotyledon). Then U/Q matching was
turned off (passive mode) and the model allowed to
restabilise, (Fig. 4(b)). Flow in the outermost layer
in the 6 cotyledon, previously restricted to 0.5
ml/min increased to match that through the others
at 2.3 ml/min, but it’s oxygen content fell from the
previous 6.1 to only 4.7 mM. Flow in the chorionic
vein collecting from all three cotyledons then increased from 19.4 to 21.4 ml/min but the mixed
oxygen concentration decreased from 7.5 to 6.9
mM. Fig. 4(c) shows the corresponding events in the
maternal circuit. In dynamic mode, extraction effectively stops when maternal blood has been extracted down to 7.4 mM but in passive mode there
is no limitation and extraction continues down to
6.8 mM.
518
Discussion
The placenta is widely thought of as a passive organ
in which blood flow depends only on the pressure
difference between the umbilical arteries and vein
connecting it to the fetus and it’s total flow resistance. Flow resistance is considered to be simply
dependent on it’s original development vascular
pattern and its developmental history. Various
authors have suggested that some form of flow
matching similar to that in the postnatal lung might
exist because placentas with areas of spiral artery
failure often still return blood of good oxygenation,
albeit of reduced flow. The first question was “do
suitable mechanisms exist?”. Two were recognised,
direct action of O2 on vascular smooth muscle in
stem villi, and indirect action by syncytio-trophoblastic metabolic products. For the latter we followed the suggestions of Myatt et al. [4] that
syncytio-trophoblastic production of NO might
form the control variable in some form of placental
flow regulating mechanism. Recent in vivo studies
show that NO lifetime in plasma is in the range of
seconds to minutes [5], and that some plasma
components may act as NO carriers longer lifetimes
(S-nitrosothiols, RSNOs). They are relatively unstable and are easily induced to reversibly degrade
releasing NO and the corresponding disulphide
[19], and are potent inhibitors of vascular and
gastrointestinal smooth muscle. Functionally, such
a transport mechanism extends the half-life of a
proportion of any NO produced and explains why
NO introduced into the brachial artery can dilate
arteries and arterioles in the forearm several seconds later. It also means that NO, dependent on
maternal intervillus blood status, must be considered a valid signal anywhere in the placental vascular structure as Myatt et al. [4] suggested. NO
would be carried back through to the intermediate
villi and stem veins, diffuse around the accompanying arteries, and induce them to relax, in proportion to NO concentration, from their natural
(constricted) state. Direct action of O2 on the cell
membrane K+ channels of vascular smooth muscle
in the walls of villi would, from a modelling point of
view produce the same effect at the same sites so
the more complex indirect configuration was used
in this report. In vivo it is anticipated that if the
mechanism is direct O2 response should start
within a few seconds, if indirect it would be much
slower.
The next question was “Are the physical and
mechanical configurations within cotyledons compatible with such a system”. Examination of plastic
casts of normal placental cotyledons showed that
Talbert, Sebire
artery vein pairs of about 100 lm lumen diameter
run parallel and about 100 lm apart in intermediate villi within cotyledons. Stem arteries and vein
lumen casts were about 400 lm diameter with a
similar relative spacing. This implies that in vivo
their vascular walls were virtually in contact over
much of their length, meeting the requirement for
diffusion sites where arterial smooth muscle could
be relaxed by a diffusible substance carried back
from the syncytium. Failure of adequate intervillus
flow would then remove the relaxation normally
induced by this NO allowing the arteries to constrict, and so reducing flow to that area.
When models of such cotyledonary structures
were connected to form the whole placental model
and the fetal model two significant effects were
seen. Firstly, although umbilical vein oxygenation
was maintained at a higher level with flow matching active, it was at the expense of reduced flow.
Secondly, when cotyledons responded to intervillus
hypoxia the hydrostatic pressure in their capillaries
was reduced allowing water to enter and flood the
fetus. The latter led to a separate study of transplacental water factors reported separately [12].
The relevant factor here is that if the fetus can
control placental venous resistance by a circulating
hormone it can adjust mean villus capillary pressure to compensate for any disturbance of water
balance, and maintain it’s body composition at an
optimum level. Adding such a control mechanism
enabled the flow matching study to proceed.
It then has to be asked, if matching involves
restricting flow through poorly oxygenated cotyledons so that umbilical vein flow is reduced, to the
extent that total O2 delivery to the fetus is actually
reduced, could there ever have been any evolutionary advantage selecting for this? It might be
thought that if the placenta has become only
marginally efficient the fetus must need all the
oxygen it could get, but in fact pO2 is very important at the point of delivery. When oxygen is unloaded through the fetal capillaries it has only just
started the last stage of its journey. It then has to
pass through the capillary walls, interstitium,
muscle fibres and other O2 consuming cells, until it
meets oxygen diffusing in the opposite direction
from neighbouring capillaries (the Krough radius;
20). The rate at which diffusion takes place, and
hence the concentration of oxygen available to
cells midway between capillaries, depends on the
concentration gradient from the blood plasma in
contact with the capillary wall to that at cells at
the Krough cylinder margin. All else being equal
this is proportional to the difference of partial
pressure of oxygen (pO2) in the blood and at the
cell membrane, not necessarily the oxygen con-
The dynamic placenta
tent. For instance, suppose the haemoglobin content of the blood were doubled, but the molecules
were loaded to the same mean partial pressure.
The plasma in contact with the capillary wall,
which does the actual transfer, would be at the
same partial pressure. More oxygen would pass
down the lumen to other parts of the circulation,
but cells at the Krough margin would have the same
O2 delivery. In highly active tissue such as the
heart and brain, high oxygen partial pressures are
vital to drive oxygen sufficiently quickly to cells
midway between capillaries. In the fetus vital tissues are predominately supplied from the left
heart to which umbilical blood streams. Therefore
feto-placental units that optimise pO2 at the expense of total flow may have a selective vital tissue
survival advantage over any that merely maintain
maximum flow.
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