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a Chapter 9 Fetal and Maternal Cardiovascular Physiology 115
dynamic alterations during pregnancy similar to
those observed in humans. Although these animal experiments
allow us to emphasize some common fundamental
control mechanisms in both the development
and control of the uteroplacental circulation, it
should be appreciated that significant variations (e.g.,
type of placentation) are known to exist among species.
Blood flow to the uterus during early pregnancy
has been most comprehensively studied in the pig
[31]. In this species, a sharp peak of uterine blood
flow to the pregnant horn is observed on days 12 and
13 after mating, before definite attachment of the embryo
occurs, suggesting an early, local effect of the
blastocyst on uterine blood flow. This phase is followed
by a progressive and dynamic increase beginning
on day 18 or 19, which corresponds to the day
of implantation and the initiation of placentation.
Studies in sheep have correlated the changes in
uteroplacental blood flow to the growth and development
of the placenta of the fetus and have provided
some insight into the long-term regulatory mechanisms
controlling the development of the uteroplacental
circulation. In the nonpregnant ovariectomized
sheep, uterine blood flow is approximately 25 ml/min
and increases to 400 ml/min at midpregnancy when
definite placentation is complete. Absolute uterine
blood flow increases beginning at midpregnancy until
term to reach a level of 1,500 ml/min (term is at approximately
146 days), although uterine blood flow
per gram of total uterine (and fetal) weight remains
constant. These values of uterine blood flows represent
approximately 0.5%, 8.0%, and 20.0% of cardiac
output, respectively [19, 32].
The distribution of blood flow within the gravid
uterus was measured using the radiolabeled microsphere
technique [33]. At an early stage of gestation
(second month) the myometrium and endometrium
receive approximately 70% of total uterine blood flow.
During the third month of pregnancy the placenta attains
its maximum size and becomes the major component
of uterine weight, and placental blood flow represents
approximately 60% of the total. During the
final 2 months there is no further placental growth,
but fetal weight increases exponentially; during this
stage of gestation there is a three- to fourfold increase
in placental blood flow, and near term it accounts for
80%±90% of total uterine blood flow [19, 33].
These observations suggest that the longitudinal
hemodynamic changes in the uteroplacental circulation
are directly related to the growth rate of the tissue
it supplies. There are two stages in the growth
and development of the uteroplacental circulation.
The first stage extends from the time of implantation
through 80±90 days' gestation and is reflective of the
period of placental growth and development of new
blood vessels [34]. The second stage extends over the
last 2 months of pregnancy. During this period there
is no further growth of the placenta and no formation
of new blood vessels, as reflected by the number
of maternal and endothelial cells [34]. There is an increase
in the cross-sectional area of the uterine vascular
bed, however, and placental perfusion continues
to increase until term to accommodate fetal growth.
The progressive increment in uteroplacental perfusion
and the progressive decline in uterine vascular resistance
during the second stage of pregnancy are secondary
not only to vasodilation of the uteroplacental
vascular bed (inasmuch as studies in unanesthetized
sheep have shown that the vasculature is nearly maximally
dilated [35±38]) but also to the gradual increase
in the luminal diameter of the resistance vessels. Indeed,
there is rapid, active growth in the uterine arterial
wall. The threefold increase in the internal radius
of the uterine artery is not merely the result of passive
dilatation, as wall thickness is unchanged; there
is hypertrophy of its vascular smooth muscle and a
decrease in its collagen fraction [39].
Regulation of Uteroplacental Circulation
The regulatory mechanisms that promote the described
sequence of changes in uteroplacental blood
flow by influencing the formation and growth of the
uteroplacental blood flow are poorly understood. Putative
regulatory agents include steroid hormones, angiogenic
factors, growth factors, and other unknown
substances of fetal or maternal origin.
Steroid Hormones and Vasoactive Agents
The uterine vasculature is sensitive to estrogens [37,
40, 41]. Estradiol is a potent uterine vasodilator in
nonpregnant sheep, and the magnitude of increase of
uterine blood flow at early gestation can be produced
by injecting estradiol into nonpregnant sheep. Exogenously
administered estradiol also increased placental
blood flow, although the observed percentage
increase from baseline is not striking as it is in the
nonpregnant state. Furthermore, the response to estradiol
appears to be more pronounced during early
pregnancy than at later pregnancy [37], suggesting
that during later pregnancy the placental vasculature
is almost maximally dilated. Uterine blood flow response
to estrogen is probably mediated largely by
nitric oxide (NO), which can stimulate production of
vascular endothelial growth factor (VEGF) and basic
fibroblast growth factor (bFGF) [42, 43].
The role of progesterone in regulating the development
of uteroplacental circulation and the rate of
uterine blood flow is even more complex. In the
sheep, progesterone given in pharmacologic doses in-