Review Fisiopatologia PEL

Drug Discovery Today Volume 00, Number 00 November 2017 REVIEWS
Teaser Special physiology and precise pathophysiology in placental vessels are crucial in
understanding mechanisms of pregnant hypertension and the basis for precision medicine
targeting preeclampsia.
What is precise pathophysiology in
Reviews KEYNOTE REVIEW

development of hypertension in
pregnancy? Precision medicine requires
precise physiology and pathophysiology
Qinqin Gao1,z, Jiaqi Tang1,z, Na Li1, Bailin Liu1, Qinqin Gao received her
PhD in biochemistry and
Mengshu Zhang1, Miao Sun1 and Zhice Xu1,2 molecular biology from
East China Normal
University, China. Since
1
Institute for Fetology, First Hospital of Soochow University, Suzhou, China 2013, she has served as an
2 assistant professor in the
Center for Perinatal Biology, Loma Linda University, CA, USA
Institute for Fetology at the
First Hospital of Soochow
It is widely accepted that placental ischemia is central in the evolution of University. DNA methylation/histone modifications
and epigenetic reprogramming are her areas of
hypertension in pregnancy. Many studies and reviews have targeted expertise. Her current research focuses on the
mechanisms in developmental programming of adult
placental ischemia to explain mechanisms for initiating pregnancy diseases, and the etiology of pregnancy complications,
hypertension. The placenta is rich in blood vessels, which are the basis for especially preeclampsia.
developing placental ischemia. However, is the physiology of placental Miao Sun, PhD, is
Associate Director,
vessels the same as that of nonplacental vessels? What is the Institute for Fetology, First
Hospital of Soochow
pathophysiology of placental vessels in development of pregnancy University. She obtained
hypertension? This review aims to provide a comprehensive summary of her medical genetics
training and conducted
special features of placental vascular regulations and the scientific research at
Peking Union Medical
pathophysiological changes linked to preeclamptic conditions. College, Johns Hopkins University and Emory
Interestingly, some popular theories or accepted concepts could be based University. Her main research interest focuses on
molecular mechanisms underlying birth defects,
on our limited knowledge and evidence regarding placental vascular including monogenic genetic diseases and fetal origin
disorders. She discovered that 5 hmC is a major
physiology, pharmacology and pathophysiology. New views raised could epigenetic response to hypoxia conditions for fetuses
offer interesting ideas for future investigation of mechanisms as well as in utero, and proposed the ‘Three Hits’ hypothesis for
fetal origins of adult diseases.
targets for pregnancy hypertension.
Zhice Xu received his
PhD at University of
Cambridge, UK, and his
postdoctoral training at the
Introduction University of Iowa, USA.
As the most common medical syndrome of human pregnancy, hypertensive disorders (especially Then he was an assistant
professor in the
preeclampsia) are a major cause of maternal and perinatal mortality. This syndrome affects Department of Obstetrics
millions of women worldwide who had normal blood pressure before pregnancy (5% of all and Gynecology at the
School of Medicine, UCLA, later serving as Associate
pregnancies) each year, with an increased tendency in the past decade [1]. Why can pregnancy
Professor and Professor at the Center for Perinatal
make blood pressure abnormal in these women? Although this question has puzzled doctors and Biology, Loma Linda University, USA. He is currently
scientists for many years without precise answers, there is a widely accepted consensus that the Professor and Director for the Institute for Fetology
at First Hospital of Soochow University, China. The
placenta is key in pathogenesis of pregnancy hypertension (PH), because occurring and ending of Institute is leading in fetal medicine in China, especially
PH is closely linked to appearance and disappearance of the placenta, and only removal of the in fetal cardiovascular physiology and
pathophysiology. His main scientific interests are fetal
placenta abolishes symptoms in preeclampsia. Notably, only the placenta, not the fetus, is medicine, placental circulation and pregnancy
required for progression of PH [2,3]. Thus, most previous investigations on the mechanisms of PH complications.
Corresponding authors: Sun, M. (miaosunsuda@163.com), Xu, Z. (xuzhice@suda.edu.cn)

z
Authors contributed equally to this work.
1359-6446/ã 2017 Published by Elsevier Ltd.

https://doi.org/10.1016/j.drudis.2017.10.021 www.drugdiscoverytoday.com 1
Please cite this article in press as: Gao, Q. et al. What is precise pathophysiology in development of hypertension in pregnancy? Precision medicine requires precise physiology and
pathophysiology, Drug Discov Today (2017), https://doi.org/10.1016/j.drudis.2017.10.021
DRUDIS-2116; No of Pages 14
REVIEWS Drug Discovery Today Volume 00, Number 00 November 2017
tended to target the placenta, and it has been widely accepted that The placenta is considered as the center for initiation of patho-
placental ischemia as an important initiating event in preeclamp- logical changes in development of PH. As an organ, two major
sia and thus a key stage in the mechanisms underlying PH [4,5]. functions of the placenta: the maintenance of proper circulation
The placenta connects the developing fetus to the uterine and release of all kinds of biofactors, rely on its blood vessels and
system, with several crucial roles: (i) transporting gases, nutrients various placental cells. This review only focuses on placental
and waste between the maternal and fetal circulation systems; (ii) vessels because this organ is rich in blood vessels. The fact is that
immuno-protection and releasing of chemicals necessary for preg- all current theories on the primary mechanism causing PH have
nancy [6]. It is undeniable that, as a new feto-maternal vascular accepted the hypothesis called placental ischemia [4,5]. In previ-
organ, abnormalities in placental vascular functions must have ous reports, anatomical or histological studies revealed vascular
dramatic effects on the fetus and the pregnant woman [7]. Over remodeling in spiral arteries, either via immuno-dysfunction or
the past decades, the hypothesis for the development of PH has other causes [16,17]; molecular experiments showed abnormali-
been focused on placental ischemia. Whether it is caused by ties in producing or releasing biofactors [12,13]; physiological and
remodeled spiral arteries or another factor-impaired placental pharmacological investigations demonstrated changes in placen-
blood flow complication, placental ischemia is considered as tal circulation [18]. All of those studies point the outcome out as
the center for releasing various chemicals or signals, leading to placental ischemia. Therefore, placental ischemia was blamed for
maternal hypertension [4,5]. This concept has been generally causing changes in biosignals influencing blood pressure and
outlined as the ‘two-stage theory’. The first stage proposes that inducing PH (Fig. 1).
numerous factors, including genetic, immunological and environ- Thus, placental ischemia seems a reasonable cause of PH, as well
mental influences, might cause abnormal placentation and subse- as a potential target for treatments of PH. So far there is no
quently reduce blood flow, leading to placental ischemia [8–10]. precision medicine for the treatment or prevention of PH, because
Then, it is considered that during the second stage the under- the pathophysiology of PH is unclear. If placental ischemia is a
perfused placenta releases chemicals or molecules into the circu- truly initial event in causing PH, future investigations should focus
lation. This includes antiangiogenic factors [such as soluble fms- on how placental ischemia was produced. Assuming placental
like tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng)] [11], ischemia or hypoperfusion is central in causing PH, blood vessels
inflammatory mediators [12] and angiotensin II type I receptor and their pathophysiology would be crucial. Thus, this review
activating autoantibodies (AT1-AA) [13]. Such bioactive factors in focuses on physiology and pathophysiology of placental vessels,
turn cause an excessive inflammatory response and an oxidative reviewing what has been investigated in comparative physiology
stress environment in the vasculature [14,15], resulting in a cas- between placental and nonplacental vessels, as well as pathophys-
cade of endothelial activation and dysfunction, with typical fea- iology between normal and PH placental vessels. We hope this
tures of increased vasoconstriction and decreased vasodilatation review generates some interesting and important clues for direc-
[5]. Abnormalities in the profiles of constrictive phenotypes in- tions of future studies and treatments for PH. In addition, using PH
crease maternal blood pressure and peripheral vascular resistance as an example to demonstrate precise physiology and pathophysi-
in organs, including the placenta [4,5]. ology is crucial in precision medicine based on genes or molecules.
Genetic or immuno-dysfunction, etc.
Artery remodeling
?
Placenta
Endothelial dysfunction
Placental poor perfusion
Placental ischemia
Chemicals or molecules released into circulation
Maternal blood pressure

Drug Discovery Today
FIGURE 1
Summary of current theories on the development of hypertension in preeclampsia.
2 www.drugdiscoverytoday.com
Placental vascular bed Vascular reactivity of endogenous vasoactivators in

A successful outcome of pregnancy is dependent on sufficient normal and preeclamptic placenta
placental perfusion and adequate blood flow via utero-placental Hypertension is a disease mainly based on dysfunction of blood
and feto-placental circulatory systems. Generally, the utero-pla- vessels. Because the placenta is assumed as a center in initiation of
cental circulation starts with the maternal blood flow into the PH, to study the primary mechanism underlying PH or to investi-
intervillous space through uterine spiral arteries. After exchange gate placental ischemia without touching placental vessels is not
of oxygen and nutrients in the intervillous space, the in-flowing possible. To learn how placental blood flow could be reduced or

maternal arterial blood pushes deoxygenated and nutrient-de- how placental ischemia might be generated in pathophysiology,
pleted blood into the endometrium and then flows back to the we should understand normal as well as special physiology of
maternal circulation through uterine veins. The feto-placental placental vessels, and understand how placental vascular changes
circulation allows umbilical arteries to carry deoxygenated and can induce ischemia. This will be reviewed and discussed through
nutrient-depleted fetal blood from the fetus to the villous core various vasoactivators in the following sections.
fetal vessels. After exchange of oxygen and nutrients, the umbili-
cal vein carries fresh oxygenated and nutrient-rich blood back to Prostanoids
the fetal circulation [6]. The feto-placental circulation is com- Prostanoids are a subclass of eicosanoids consisting of the pros-
posed of two umbilical arteries, one vein and a placental vascular taglandins (PG), thromboxanes (TX) and prostacyclin PGI2. As
tree, which includes chorionic plate (fetal stem villous) arteries potent vasoactive agents, PG and TX often cause constriction in
and their branches, terminal villi and veins [6]. The placental vascular smooth muscle cells (VSMCs), whereas PGI2 has powerful
vascular bed is often regarded as a comparatively low-resistance vasodilator effects [31–33]. Do PG and PGI2 have the same physi-
circulation in which blood flow is determined by the fetal cardiac ological roles in placental arteries as they do in nonplacental
output, contributing to the circulation, when maternal arterial vessels? Unfortunately, studies and data so far could not reach a
pressure propels maternal blood flow through the placenta. clear conclusion, like that available for nonplacental vessels. How-
Therefore, placental vascular tone is essential for maintaining ever, our new study (unpublished data) strongly indicates that
the adequate placental blood flow and volume. Because placental they are not the same. For example, PGI2 does not show any
vessels lack automatic innervation [19], local vasoconstrictor and significant vasodilation effects in normal human placental vessels
vasodilator systems, including prostanoids, endothelins (ET), (large and the third or fourth branches of small vessels), which is
histamine (HA), serotonin (5-HT), catecholamines, renin-angio- certainly true in nonplacental vessels. This means the main vaso-
tensin system (RAS) and nitric oxide (NO), are of paramount dilator PGI2 from prostanoids has special physiological roles in the
importance for controlling placental vasoactivities and blood placenta, which are not for vascular dilation. Of course, because
flow in the placental circulation [20,21]. As an endocrine organ, this requires further investigation, future work and ongoing stud-
the placenta can produce numerous vasoactivators that are re- ies can answer such important and basic questions for placental
leased into the circulation, dominating the regulation of placen- circulation that should be well understood when dealing with
tal vascular reactivity [22–24]. The balance between vasodilators mechanisms and pathophysiology of PH.
and vasoconstrictors in placental circulation is crucial for a Prostaglandins
homeostatic balance. Therefore, the compromised and abnormal PG are a group of physiologically active lipid compounds and there
constriction and relaxation of the placental vasculature must are two different types (PGE2 and PGF2) that have significant
influence blood flow in the placenta, a root cause for placental effects on coagulation and vascular tone [33]. The potent effects
ischemia, leading to an abnormal course of pregnancy such as of PG in modulating vascular tone have naturally led to an
preeclampsia. investigation of their roles in preeclampsia. However, although
Remodeling of placental arteries, like spiral arteries, was sug- much effort has been made in attempting to link altered concen-
gested as a main pathological cause for local ischemia [16,17,25]. tration and activity of PG to the development of preeclampsia, the
Either placental vessels became narrow [26,27] or reduced vas- results have been largely equivocal and conflicting. A study by
cular branches [26,28–30], could induce poor blood flow or Robinson et al. in 1979 stated that the concentrations of PGE2 and
ischemia in the placenta. Although, beautifully histological PGF2 in the placenta obtained from preeclampsia were significant-
demonstrations of remodeled placental vessels such as altered ly lower than the control [34], whereas Hillier and Smith found no
vascular diameters or vessel number were shown in limited difference in PG levels between normal and preeclamptic pla-
papers, notably, most histological evidence presented in pub- centas [35]. In human placental vessels, PGE2 produced weak or
lications, no matter how wonderful, tends to select extreme no responses, whereas PGF2 could cause moderate vasoconstric-
samples between compared groups, and sample number could tion [36]. Ezimokhai et al. reported that the vascular reactivity of
be limited in general. As we will emphasize again and again human placental vessels to PGF2 was enhanced in preeclampsia
below, in studies of the human placenta sample size is crucial [37]. However, studies by Inayatulla et al. and Allen et al. showed
and affects analysis owing to huge variation in genetics, diets, that there was no difference in response to PGF2 between normal
living habits, body weight, health conditions and medical com- and preeclamptic placental vessels [36,38].
plications. Thus, a good reliable quantitative analysis of anatom- PGI2
ical consequences of placental vascular remodeling in a relatively PGI2 is a prostanoid produced from the metabolism of arachidonic
large number of human samples is required in studies of placen- acid by cyclooxygenase in vascular endothelial cells. Endotheli-
tal ischemia in pathology and its possible relationship to the um-derived PGI2 can contribute to hemodynamic and vascular
development of PH. changes during pregnancy [39]. During normal pregnancy, the
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production of PGI2 was found to be increased as pregnancy in hypertensive and normotensive pregnancies [53]. Meanwhile,
progresses, reaching a peak in the third trimester [40]. Various placental TXA2 receptors were found to be similar between pre-
vascular tissue was reported to produce PGI2, including the pla- eclamptic and normal pregnancies [54].
cental and umbilical vessels [24]. An in vitro study suggested PGI2 In addition, numerous studies showed that a delicate balance
had an important role in the control of placental circulation [39]. exists between PGI2 and TXA2 to maintain a normal vasomotor
PGI2 production and activity were significantly depressed in pla- tone in normal pregnancy. In preeclampsia, the plasma ratio of 6-
cental vascular tissue from severe preeclampsia in comparison to keto-PGF1a (a stable metabolite of PGI2) to TXB2 was significantly
normal pregnancy [41]. However, studies by Ylikorkala et al. decreased [48], and placental TX metabolite formation was
showed that there was no difference of PGI2 levels in maternal markedly elevated accompanied by a similar PGI2 production,
circulation and the placenta between normal and preeclamptic which could be against the actions of TXA2 [55]. The imbalance
pregnancies [42]. PGI2 could cause moderate vasodilation in between placental TXA2 and PGI2 is shifted in preeclampsia to the
human placental vessel rings and perfused feto-placental lobules conditions that favor feto-placental vasoconstriction. In pre-
[21,32]. Kossenjans et al. reported that PGI2-induced dilation was eclampsia, decreased PGI2 and/or increased TXA2 or the imbal-
reduced in perfused preeclamptic placental cotyledon [43]. By ance of PGI2 to TXA2 were assumed to contribute significantly to
contrast, another two studies reported that, whether placental increased vasoconstriction in the placenta.
vessel rings or perfused feto-placental lobules, there were no Together, previous studies on prostanoids in placental blood
differences in dilatation by PGI2 in placental vessels obtained vessels and preeclampsia were interesting; however, the data
from either normal or preeclampsia samples [38,44]. reported were controversial. This special phenomenon in a study
Thromboxanes of placental blood vessels is common, but why? There are multiple
TX are a member of the family of lipids known as eicosanoids. The reasons. First, those experiments used human samples with dra-
two major TX are TXA2 and TXB2. TXA2 is very unstable in matic variations in genetic, environmental, living styles and in-
aqueous solution, and hydrolyzed within 30 s to biologically dividual differences, and the sample size was usually too small in
inactive TXB2. TXB2, a stable metabolite of TXA2, gradually general. For example, as indicated in Table 1, sample size for the
increases with gestational age [45]. As a potent vasoconstriction experimental group was limited; sometimes even 5–9 for a group,
agent, TXA2 activates phospholipase C via its receptors, leads to which was insufficient to make solid conclusions for placental
activation of protein kinase C and causing constriction in VSMCs. vascular physiology and pathophysiology in PH. This was also a
During pregnancy, placenta trophoblast cells and the villous core major cause for confused and inconsistent data among previous
can produce TXA2 by TXA2 synthase [46]. In normal pregnancy studies. Second, many functional studies were not performed on
there was no significant difference in the plasma TXB2 levels placental vessels directly, whereas many works that were claimed
between antepartum and postpartum, whereas in hypertensive to be aimed at placental vessels were actually targeted on mole-
groups plasma TXB2 showed a significant decrease after delivery cules and chemicals in placental tissue instead of blood vessels.
[47]. In women with preeclampsia, plasma TXB2 was similar to Based on the background with only limited experiments and
that in normotensive pregnant women [48]. However, TXA2 and insufficient samples of generated data, which were often contra-
its metabolite formation, as well as TXA2 synthase, were signifi- dictory to each other, the real pathophysiology of placental vessels
cantly increased in preeclamptic placenta compared with normo- in PH is still largely unclear.
tensive placenta [49,50]. TXA2 analog U46619 markedly increased
perfusion pressure in the placental lobule and constriction of Endothelins
placental vessels [31,51]. Several studies demonstrated that Endothelins are 21-amino-acid peptides produced primarily in
U46619-mediated perfusion pressure, as well as U46619-induced endothelial cells and have been found to be the most potent
maximum constriction of placental chorionic plate vessels, was and long-lasting vasoconstrictor yet discovered. Three types of
significantly attenuated in placentas from the preeclamptic preg- ET (ET-1–3) have been identified with ET-1 being widely distribut-
nancy compared with normotensive pregnancy [43,44,52]. How- ed in the human placenta [56]. ET-1 presents contraction
ever, Kwek et al. reported that the maximum effect and EC50 responses through Type A (ETA) and Type B (ETB) in VSMCs
caused by U46619 in placental chorionic arteries was equipotent [57]. During pregnancy, ET-1 is the most potent vasoconstrictor
TABLE 1
Vascular effects of ACh in the human placenta
Substance Sample type Vasoactive effect Sample size Refs a
ACh Human perfused placental cotyledon Vasodilatation N = 6, n = 6 [148]
Human placental arteries Vasodilatation N = 12 [149]
Human perfused placental cotyledon Vasoconstriction N = 5, n = 5 [153]
Human perfused placental cotyledon Vasoconstriction N = 3, n = 3 [152]
Human perfused placental cotyledon No effects N = 4, n = 4 [150]
Human perfused placental cotyledon No effects N = 5, n = 5 [138]
Human placental artery rings No effects N = 10, n = 10 [77]
Human placental vein rings No effects N = 4, n = 4 [151]
Human placental artery rings No effects N = 89, n = 217 [132]
Abbreviations: N, number of placentas; n, number of vessel rings or placental cotyledons used in the studies; ACh, acetylcholine.
a
Except for Ref. [132], samples in were: N = 3–6, the maximum number of vessel rings or placental cotyledons was 10.
in maternal and placental arteries and has important physiological whereas, in preeclampsia, plasma HA was increased [73]. Notably,
and pathological roles in regulating vascular resistance [57]. In compared with the control, a higher HA concentration and a lower
normal pregnancy, plasma ET-1 decreases with increasing preg- DAO activity were in the placental tissue in preeclampsia, contrib-
nancy age and remains at a low level until delivery [58]. Multiple uting to the increased HA in the maternal circulation [71,73,74].
studies stated that in preeclamptic women circulating plasma ET-1 Data from this literature suggested that HA could be involved in
levels were elevated [59,60]. A positive correlation between circu- the pathogenesis of preeclampsia-complicated pregnancies.
lating plasma ET-1 and severity of symptoms in hypertensive HA exerts multiple effects primarily by binding to its four

pregnancy was noted [60]. In placental tissue of preeclamptic receptors [HA-1 receptor (H1R), H2R, H3R and H4R] in various
pregnancy, ET-1 was higher and correlated positively with severity tissues [69,71]. As a potent vasoactive agent, HA causes vascular
of symptoms [56]. In early-onset preeclamptic placenta, the mRNA contraction via directly binding to H1R, whereas vasodilatation
expression of ET-1 and its receptors (ETA and ETB) were increased occurs via direct activation of H2R on VSMCs [69]. A significant
[61]. However, it was also reported that placental ET-1 and its amount of HA existed in the placenta, with a higher level in the
precursors (preproendothelin, big endothelin) in preeclamptic preeclamptic placenta, and is considered as regulating vascular
pregnancy were similar to that in normotensive pregnancy [62]. tone and affecting maternal-placental circulation. Szukiewicz et al.
Information about placental vascular reactivity to ET-1 is still found that there were no differences in the increase of perfusion
limited. Read et al. reported that there was no difference in pressure following administration of HA between normal and
response to ET-1 in the perfusion placenta obtained from normo- preeclamptic placenta [67]. Bertrand and St-Louis showed that
tensive and preeclamptic women [44]. Another study reported no the overall vasoactivities of placental vessels to HA were not
significant differences in EC50 or maximum ET-1-induced affected in preeclampsia, whereas the maximal response to this
responses in placental artery rings between normotensive and amine was decreased in preeclamptic placental vessels [75].
preeclamptic women [38]. Notably, the number of objects used
was small. In addition, even if it is certain that ET-1 can induce 5-HT
vasoconstriction in placental vessels, whether that is exactly the 5-HT is a monoamine neurotransmitter and plays a crucial part in
same as the situation in nonplacental vessels is uncertain owing to placentogenesis and embryogenesis. 5-HT synthesis in the placen-
a lack of such physiological comparisons so far. For example, ta is crucial for fetal development [76]. The major effect of 5-HT in
whether ET-1-stimulated placental vessel contractions are stronger most nonplacental small blood vessels is contraction [63]. 5-HT
or weaker or the same compared to nonplacental vessels is still can also cause contraction in placental arteries and increase the
overlooked. To understand such vascular physiology is important perfusion pressure through 5-HT receptors [77]. It seems there are
to understand possible special characters for placental vessel func- no significant differences in 5-HT-mediated vasoconstrictions be-
tions as well as dysfunctions. tween nonplacental and placental vessels. In general, 5-HT-in-
duced vasoconstrictions in the placenta appear to be stronger than
Histamine those caused by catecholamines and angiotensin II (Ang II).
HA is an organic nitrogenous compound derived from l-histidine There are seven families of 5-HT receptors (5-HT1–7). Among
by histidine decarboxylase. In nonplacental vessels, the physio- them, 5-HT2 receptors have been identified in human placental
logical roles of HA are clear and different depending on various tissue and participated in the regulation of vascular tone [77,78].
organs. In general, HA can act as a stimulator for vasoconstrictions In preeclampsia, plasma 5-HT was significantly higher than that in
in mesenteric and cerebral arteries [63,64], in other tissues such as normotensive pregnancy [79,80]. Plasma 5-HT can be effectively
porcine retinal and carotid arteries the main effects of HA are taken up by platelets through a storable transport process. Com-
vasodilation [65,66]. For the placenta, some studies demonstrated pared with normotensive pregnant women, the maximum veloci-
HA can induce concentration-dependent contractions in isolated ty values for platelet 5-HT uptake were significantly higher in
human placental vessels [67,68], whereas the study by Mills et al. preeclampsia [79]. In human placenta, serotonin transporter
reported HA can induce endothelial-dependent relaxation in hu- (SERT) can reuptake 5-HT and terminate the effects of 5-HT
man chorionic plate artery rings [69]. However, our recent study [81]. There was no difference in placental SERT levels between
suggests that HA did not present dilation effects to 5-HT or other the normal and hypertensive pregnancies [82]. 5-HT in the pla-
stimulator-produced vasoconstriction in human placental vessels, centa can be degraded by monoamine oxidase A. The expression
regardless of arteries being large or small (unpublished data). In and activity of monoamine oxidase A were found to be very low, or
light of this, placental vessels are different from nonplacental ones almost negligible, in severely preeclamptic pregnancies compared
in physiological functions, which are not well understood. Wheth- with normal pregnancies [83]. These data supported the hypothe-
er and how those special physiological characters play parts in sis that placental 5-HT was higher in pregnancy-induced hyper-
normal pregnancy as well as in PH is worth further investigation. tension. Cruz et al. reported that placental vessel segments from
HA has been implicated in regulatory processes of pregnancy, the preeclamptic patients exhibited an increased maximal isomet-
and in the pathogenesis of preeclampsia [70]. During pregnancy, ric tension and sensitivity to 5-HT [84]. Other studies showed that
the placenta produces a significant amount of HA and HA-degrad- there were no differences in 5-HT-induced contraction responses
ing enzyme diamine oxidase (DAO) in mast cells [71]. DAO is in placental vasculature obtained from either the normal pregnan-
supposed to act as a metabolic barrier to prevent excessive entry of cy or preeclampsia patients [38,44]. Nevertheless, Bertrand and St-
HA from the placenta into the maternal or fetal circulation. In Louis reported that placental vascular reactivity to 5-HT was
normal pregnancy, plasma HA levels were decreased with increas- reduced in preeclampsia [75]. 5-HT-mediated constrictions are
ing gestation, reaching a low point in the second trimester [72], reduced or equipotent in preeclamptic placental vessels compared
with normotensive pregnancy, which could compensate for the systemic vasoconstrictor, the high vasopressin values in the circu-
increasing of 5-HT in the plasma and placenta. Again, this was lation could cause remarkable vasoconstriction in preeclampsia.
typical vascular pathophysiology in the placenta as noted. Among Maigaard et al. observed that, compared with all the other vaso-
an already limited number of direct functional studies on placental constrictors tested, vasopressin induced relatively moderate vaso-
vessels, all kinds of conflicting data existed regarding placental constrictor responses in chorionic plate arteries [88]. There were
vascular responses to vasoactivators. For instance, there have only two studies investigating constriction responses to vasopressin
been a few publications comparing placental vascular functions in between preeclamptic and normal placental vessels. Wareing
response to 5-HT between the control and preeclamptic pregnancy and Baker reported that, compared with the normal placenta,
to date. We can see all three kinds of vascular functional responses the maximal vasoconstriction induced by vasopressin was reduced
reported: increased, decreased and unchanged responses to 5-HT in the preeclamptic placenta [52], whereas Ong et al. showed that
in the placenta of preeclamptic pregnancies. A similar phenome- the constriction responses to vasopressin did not differ between
non also existed in a study of other vascular stimulators such as the preeclamptic and normal pregnancies [93].
catecholamines and AngII in the placenta. This is one of the main
reasons why knowledge about the real pathophysiology for devel- Catecholamines
opment of PH remains unclear. An immediate question is there- Catecholamines are a monoamine group derived from the amino
fore raised: what are the major causes for that phenomenon in the acid tyrosine, and include adrenaline, noradrenaline and dopa-
study of placental vessels? At least two reasons could be consid- mine. During pregnancy, maternal plasma noradrenaline was
ered: (i) for those functional studies on human placental vessels, suggested to be markedly increased in the second trimester to
the sample size was too small for huge variations in human parturition as opposed to the first trimester and in nonpregnancy
subjects; (ii) for nonplacental functional vascular studies, many [94], and plasma dopamine was increased during the second
different animal models could be used, which is an excellent way trimester [94]. In preeclampsia, plasma noradrenaline levels were
of solving the concerns over sample variation in human studies. significantly higher than those of normotensive pregnancies [95];
However, in the study of physiological functions or pathophysio- however, Moodley et al. reported that plasma noradrenaline con-
logical dysfunctions in placental blood vessels, only very limited centrations were not statistically different between the preeclamp-
research has used limited animal models such as sheep placenta. tic and normotensive pregnancy, and only plasma adrenaline
Thus, future studies on placental vascular physiology or patho- values were higher in eclampsia [96]. Compared with normoten-
physiology should consider the concerns and problems men- sive pregnancy, the plasma dopamine in moderate and severe
tioned above. hypertensive pregnancy were markedly decreased [94]. The level
of noradrenaline in the placenta was increased with severity of
Oxytocin and vasopressin symptoms in the hypertensive pregnancy [97]. Tyrosine hydroxy-
In the context of pregnancy, the neurohormone oxytocin plays an lase is a rate-limiting enzyme for catecholamine synthesis, and its
important part in the regulation of parturition and lactation [85], activity and mRNA levels were greater in the placental tissue from
and has been used widely for decades by obstetricians as a utero- preeclamptic pregnancies compared with normotensive pregnan-
tonic agent. Oxytocin and its receptors are rich in the human cies [95], suggesting altered catecholamine in the placenta.
placenta [86], and its release from cultured placental cells is As the classic vasoconstrictor, catecholamine is a major regula-
regulated by certain growth factors [87]. As a vasoactive com- tor to maintain basal vascular tension in almost all peripheral
pound, oxytocin presented a concentration-related constriction blood vessels [98]. However, noradrenaline, phenylephrine, and
effect on chorionic plate arteries [88], suggesting that oxytocin dopamine produced relatively weak or no contractile responses in
could play an important part in regulating placental vascular tone placental vessels [22,68]. One recent study showed that maximal
and circulation. However, information about the reactivity of contraction induced by phenylephrine, norepinephrine or epi-
oxytocin in preeclamptic chorionic plate arteries is limited. One nephrine was significantly greater than that induced by Ang II in
interesting study in 1989 reported that oxytocin-induced contrac- various nonplacental vessels, including the aorta, mesentery ar-
tions in preeclamptic placental vessels were similar to those of teries and renal arteries [22]. However, the maximal response to
normal placenta [36]. The sample size in that study was small too. catecholamines was significantly lower than that induced by Ang
Whether or not additional experiments are required might need to II in human and sheep placental vessels, regardless of artery size
be checked. (large or small) [22]. Thus, it appears different from nonplacental
Similar to oxytocin, as a neuropeptide, vasopressin is a stress vessels where catecholamines serve as a main power in maintain-
hormone maintaining physiological homeostasis and hemody- ing vascular tone, placental vessels respond to catecholamines in a
namic stability. Vasopressin generates several crucial changes in relatively weaker pattern. Few studies have been conducted com-
the circulatory dynamics of the fetus [89]. In normal delivery, high paring catecholamine-mediated vascular responses in hyperten-
plasma vasopressin concentrations in the human umbilical cord sive and normotensive pregnancies. Studies by Allen et al. and
have been reported [89]. In the early 1950s, the role of vasopressin Inayatulla et al. indicated that there were no significant differences
in normal and abnormal pregnancies had already been considered in catecholamine-induced contractions between the preeclamptic
[90]. In 2014, two studies by Yeung et al. and Santillan et al. and normotensive placental vessels [36,38].
reported that maternal plasma vasopressin was significantly
higher throughout preeclamptic as opposed to normal pregnan- Renin angiotensin system
cies [91,92], implicating vasopressin release as a novel predictive The renin angiotensin system (RAS) is an autacoid system that
biomarker for preeclampsia in early pregnancy. As a potent has been demonstrated to have roles in the pathogenesis of
hypertension, including PH [22]. In the placenta, an intrinsic RAS or other activators are controversial. Several reasons are considered
has been well documented based on the presence of its major , including: (i) as mentioned above, sample size in those human
components, including renin, angiotensinogen (AGT), angioten- studies was too small (often only 12 or even fewer); (ii) method-
sin-converting enzyme (ACE), angiotensin-converting enzyme 2 ological limitation – some studies used a placental bath perfusion
(ACE2), angiotensin (1-7) [Ang (1-7)] and Ang II as well as its type 1 model, others used isolated vessel rings for functional assays. Both
(AT1R) and type 2 (AT2R) receptors [22,23,99]. ACE is a zinc experimental settings have their own advantages and shortcom-
metallopeptidase that converts Ang I to active Ang II. In addition ings in the study of vascular functions. In general, isolated blood

to ACE, ACE2 promotes degradation of Ang II to Ang (1-7). Ang II is vessels could show almost pure vascular functions in response to
an active peptide in cardiovascular systems, constricting arteries vasoactivators, without any influence by local surrounding tissue
and veins. AT1R is a major subtype mediating Ang-II-induced after isolation. In the case of organ tissue perfusion, vascular
vasoconstriction, whereas AT2R-mediated actions have been sug- responses could be complicated. They could be purely caused by
gested to counteract AT1R [100]. During normal pregnancy, the vasoactivators that are perfused or caused by secondary effects of
placental RAS is activated, with an increase in AGT, renin and ACE vasoactivators that induce other signals from attached tissue
levels, which could ultimately lead to a local increase in Ang II surrounding blood vessels. Thus, the same vasoactivators can
[101]. Because Ang II is well known to be a potent vasoconstrictor cause different vascular responses between isolated blood vessels
peptide, the placental RAS is, therefore, important for controlling and organ tissue perfusion. Some studies only tested vasoactivator
the placental vascular functions and blood circulation. In addi- levels in the placenta or circulation, others only determined
tion, Ang II can modulate the production of other vasoactive responses of placental vessels to vasoactivators.In particular, phys-
factors from the placental bed [102]. All those data indicate that iology and pathophysiology of the placental vascular system are
placental RAS should play a crucial part in controlling vascular not as well understood as that of the nonplacental vascular system.
resistance and blood flow in the human placenta. Under such situations, it could be easier to consider placental
Changes in the circulating and placental RAS in vessels using knowledge from nonplacental vessels. Mechanistic
preeclampsia stories based on that could be misleading.
Extensive studies have been done to determine the circulating and Owing to these limitations, we recently used a relatively larger
placental RAS in normal and preeclamptic pregnancies. In the sample size for the study on human placental vessels ( > 50 or even
maternal circulation, all other RAS components, except ACE and 100 per group for vascular physiology and pathophysiology anal-
Ang II, were generally unchanged or reduced in preeclamptic ysis). In addition, animal placenta from different species was also
women compared with normal pregnant subjects [103–105]. Se- used for some confirmation [22]. In respect to previous studies and
rum ACE was suggested to be increased in the preeclamptic wom- their findings, dramatic changes in our new methodology could
en, whereas the changes to Ang II were inconsistent in the various offer a solution to the controversy and inconsistency. Based on
reports. Some indicated that the level of Ang II was increased, such an experimental model, several important new conclusions
whereas others showed it unchanged or decreased in preeclampsia were noted: (i) compared with nonplacental vessels, vasoconstric-
[22,104,106]. In the placenta, some published studies found that tions induced by Ang II were much stronger in human and sheep
several RAS components in preeclampsia were increased, includ- placental vessels, indicating that Ang II plays a vital physiological
ing Ang II, AGT and AT1R, as well as ACE activity [107–109]. The part in the maintenance of vascular tension in the normal placen-
other reported no differences in renin, ACE or Ang II between the ta; (ii) compared with normal pregnancy, placental vascular
normal and preeclamptic placenta [110]. From such varied results, responses to Ang II were decreased in preeclampsia, associated
it is a serious challenge to reach a precise conclusion about the with reduced vascular AT1R, whereas Ang II and ACE were signifi-
mechanistic relationship between the RAS and preeclampsia. cantly increased in placental tissue and maternal circulation in
Vascular reactivity of Ang II in preeclamptic placenta preeclampsia. This suggested that the reduced Ang-II-mediated
Either circulating or placental RAS could affect vascular functions placental vasoconstrictions might cause compensatory responses,
and resistance, which could play a pathophysiological role in resulting in an increase in Ang II and ACE in the maternal
preeclampsia. In placental chorionic arteries, Ang II produced circulation that can induce hypertension in preeclampsia (Fig. 2).
contractions equivalent to 150% of the potassium-induced con- It is interesting that Ang-II-mediated placental vascular tone
traction [22]. Notably, two studies showed that there were no was reduced in preeclampsia [22], because reduced vascular ten-
qualitative differences in response to Ang II in chorionic plate sion could lead to poor blood flow or perfusion. Notably, either
arteries between the normal women and preeclampsia patients vasospasm or decreased vascular tone can promote local ischemia.
[36,38]. Odum and Broughton Pipkin reported that the isolated Whether the initiation of PH is linked to too much increased or
human chorionic plate arteries from preeclampsia in response to decreased vascular tension in the placenta is a good subject for
Ang II (1012 mol/l and above) were significantly sensitive [111]. investigation.
Benoit et al. showed that, compared with the control, responses to
Ang II were significantly increased in preeclamptic placental cho- Nitric oxide
rionic plate artery rings [112]. Contrary to these studies, Kossen- Nitric oxide (NO) is a potent vasodilator and relaxant of vascular
jans et al. and researchers from our laboratory demonstrated that smooth muscle, which is a gaseous molecule generated from the
the responses of placental vessels to Ang II were significantly conversion of l-arginine to l-citrulline by NO synthase (NOS)
reduced in the preeclamptic placenta [22,43]. [including endothelial (eNOS), inducible (iNOS) and neuronal
In reviewing previous studies on placental vessels in a link with (nNOS) isoforms]. NO acts via the cGMP/soluble guanylate cyclase
preeclampsia, placental vascular reactivities in response to Ang II (sGC) pathway in VSMCs. As a key protein in the pathway, sGC is
Ang-II-
mediated
placental
Wrong signal: vessel tone Wrong signal:
need more need more
Ang II Ang II
Maternal
Placenta Produces more Ang II side
Maternal
blood
pressure
FIGURE 2
Angiotensin-II-mediated pathophysiological mechanism in the development of hypertension in preeclampsia.
composed of four isoforms: a1, a2, b1 and b2 [113]. Endogenous plasma ADMA was significantly elevated [123,124]; however, Ehsa-
or exogenous NO can activate sGC to produce cGMP in VSMCs nipoor et al. showed a decrease in plasma ADMA levels in pre-
[114]. The increased intracellular cGMP can activate cGMP-depen- eclampsia versus normal pregnancy [121]. Because the amounts of
dent protein kinase G (PKG), ultimately leading to a decrease of ADMA released by endothelial cells are sufficient to inhibit NO
vessel contraction via inhibiting Ca2+ influx through Ca2+-activat- production, it is therefore possible that the altered concentrations
+
ed K channels [115]. Nitrites are important metabolites of NO of ADMA could be responsible for abnormalities in NO produc-
often used to indirectly determine NO production, and have been tion, which could play a part in endothelial dysfunction in pre-
shown to be increased in serum samples from normal pregnancies eclampsia. In addition, some studies reported that plasma cGMP
compared with non-pregnant women [116]. During pregnancy, levels were not different in preeclampsia from non-pregnant
NOS expression and activity were increased in human uterine women [122], whereas others reported plasma cGMP levels were
arteries, and NO production was enhanced during normal preg- significantly higher in preeclampsia [125,126], and such higher
nancy because of the increased estrogen level [117]. The plasma levels could return to the control values when blood pressure
cGMP was also found to be increased in the normal pregnancy became normal [126]. Additionally, changes in expression or
[118]. activity of NOS in the preeclamptic placenta also remain contro-
Changes in circulating and placental NO in versial. Some studies reported that there were no differences in the
preeclampsia distribution of eNOS and nNOS in placental tissue between pre-
Endothelial dysfunction is often associated with decreased NO eclamptic and normal pregnancies [127]. Others showed an in-
bioavailability owing to either decreased synthesis or increased crease in eNOS mRNA expression in the preeclamptic placenta
degradation, and changes in NO metabolism [119]. In preeclamp- [128,129]. Sooranna and Das and King et al. demonstrated that
sia, clinical studies about NO production have shown conflicting human placental NOS activity was markedly reduced in pre-
results, reporting increases [120] or decreases [121,122], which eclampsia [130,131]. Our recent work showed that l-arginine
could be the result of the difficulties in assessment of nitrite levels concentration, NO production and eNOS enzymatic activity, as
in humans. Asymmetric dimethylarginine (ADMA) is an endoge- well as expression of NO enzymes (eNOS and iNOS, not nNOS), in
nous competitive inhibitor of NOS, affecting NO production [121]. human placental tissue were significantly higher than those in
In women with preeclampsia, several investigations reported that placental vessels in the normal and preeclamptic groups, whereas
there were no significant differences in placental blood vessels [147]. It is possible that the decreased density of vascular mAChR
between the control and preeclampsia [132]. That study was the in umbilical cord contributed to the increased resistance of the
first to determine and compare NOS, NO and cGMP in placental umbilical circulation occurring in preeclampsia.
tissue and placental blood vessels in the same placenta. Different Only a few placental vascular functional experiments were
distribution between isolated vessels and surrounding tissues conducted with ACh, and the effects of ACh were confused by
indicates that NO-mediated placental vasodilatation was mainly significant variations [77,132,138,148–153], including suspicious
from placental tissue, not placental vessels [132]. This work is a relaxation [148,149], no effects [77,132,138,150,151] and constric-

good example for investigating placental functions as well as tion [152,153]. For example, Sabry et al. reported that ACh caused
problems by distinguishing placental vessels from other placental dose-dependent relaxation in human resistance placental stem
tissues. villi arteries [149]. Recent studies demonstrated that ACh showed
Vascular reactivity to NO-donating agents in no significant effects on human and sheep placental vessels, but
preeclamptic placenta caused vasoconstrictions in various umbilical vessels from human,
Bradykinin binding to endothelial B2 receptors leads to NO pro- sheep, rabbit and rats [132]. The same ACh exhibited reliable
duction, prostacyclin formation, elevated intracellular Ca2+ and endothelium-dependent vasodilatation in nonplacental vessels
formation of hyperpolarizing factors, causing relaxation in VSMCs (including sheep carotid artery, rat mesenteric artery and thoracic
[133]. Administration of bradykinin can cause hypotension, natri- aorta) [132]. This is typical evidence that placental and umbilical
uresis, arterial vasodilatation, increased renal blood flow and a blood vessels possess special physiology significantly different
decrease in total peripheral resistance [134]. Placental arteries from nonplacental vessels. Notably, this was the first study to
preconstricted by U46619 [135] and vasopressin [93] showed a use an animal model (sheep) to prove that ACh does not show
minimal vasodilatory response to bradykinin. However, studies in vasodilation in placental vessels, as a successful example using
perfused human placenta reported that bradykinin caused a sig- laboratory models to test important clinical questions in transla-
nificant increase in perfusion pressure [136,137]. Notably, Amar- tion medicine when using human samples only was not sufficient
nani et al. reported that bradykinin, at lower concentrations to answer the questions. Thus, using available knowledge from
(1020–1014 mol/l), produced a concentration-dependent de- nonplacental vascular studies to explain placental vascular data or
crease in perfusion pressure, whereas at higher concentrations it phenomenon, because information on physiology and patho-
produced an increase in perfusion pressure [138]. A significant physiology of placental vascular systems is limited, is sometimes
decrease in the bradykinin-induced vasodilation was found in the misleading.
myometrial arteries from women with preeclampsia when com- In addition, ACh exhibited no significant effects on preeclamp-
pared with normotensive pregnant women [135,139]. The incon- tic placental vessels, which was consistent with previous studies
sistent results regarding vasoreactivity by bradykinin in the showing that there was no relaxation effect by ACh on either
placenta not only demonstrate that functional characteristics of perfused placental cotyledon [138] or placental arteries or veins
placental vessels are different from nonplacental vessels but also using wire myograph [77,151], regardless of normal pregnancy or
suggest that further studies on placental vascular functions regu- preeclampsia [132]. Those data indicated that vasorelaxation
lated by bradykinin would be worthwhile. effects stimulated by endothelial NO systems in isolated placental
Acetylcholine (ACh), a classic chemical for vasorelaxation, can vessels were very weak and completely different from nonplacen-
dilate almost all kinds of normal intact blood vessels by promoting tal vessels, and suggested, for mechanisms in placental vascular
release of vasodilators, such as NO [140]. In most of the medical dysfunction in preeclampsia, the problem should not be vascular
literature, ACh is listed as a traditional and classic chemical for endothelial NO. This conclusion is extremely important in the
endothelial NO-dependent vasodilatation. ACh acts mainly by clinical study of precision medicine in the treatment of PH,
activating its receptors: muscarinic and nicotinic ACh receptors because even if the NO system is a suggested target, the targeting
(mAChR and nAChR). Five subtypes (M1–M5) of mAChR as well as place should not be at the placental vascular endothelial cells.
17 subunits (a1–10, b1–4, d, e and g) of nAChR have been Sodium nitroprusside (SNP), S-nitroso-N-acetylpenicillamine
identified. ACh was first reported to be present in the placenta (SNAP) and glyceryl trinitrate (GTN) are endothelial-independent
in 1948 [141], and played an important part in the maturation and agents that are usually used as NO donators in research of vasodi-
development of placental vessels and syncytiotrophoblasts, and lation [154]. SNP elicited significant relaxation in veins isolated
the modification of the uterus during labor [142]. Placental ACh from the human placental chorionic plate [151], and the vasodi-
content has been reported to be increased with gestational age, lation was significantly greater than that in nonplacental arterial
reaching a maximum between 21 and 24 weeks of gestation [143], segments [155] even under basal conditions. The placental vessels
after which it decreased toward term [144]. In preeclampsia, higher obtained from normotensive and preeclamptic pregnancies were
levels of ACh were reported in the placenta [145]. This change in equally sensitive to the relaxant effect of NO donor drugs (GTN,
ACh levels in preeclampsia has been hypothesized to induce SNP and SNAP) under basal conditions [155,156]. The same result
compensatory changes in the expression of its receptors. At the also appears in the PGF2a-preconstricted placental vasculature
mRNA level, the preeclamptic placenta showed an increase in [156]. A study by Ong et al. on small placental arteries using small
nAChR a2,a9,b1 and b2 subunit expression, whereas at the vessel wire myograph showed that vasorelaxation to SNP was
protein level a7, a9 and d subunits were increased compared with attenuated in preeclamptic placental vessels [93].
the control [146]. By contrast, preeclampsia was also found to be It is again that we can see the results of placental vascular
characterized by a loss of mAChR in the umbilical circulation not reactivity to NO-donating agents in preeclampsia are highly con-
accompanied by changes of the ACh catalyzing enzyme (AChE) troversial. As indicated above, such confusion might be the result
of sample size and the experimental methods. In many of those based on assumed knowledge or accepted theories, which might
functional studies, only a few samples (often no more than 6–7 per not be the real physiology and pathophysiology in the placenta.
group) were used, which should be a major concern because of
huge variation in human subjects. Therefore, our recent vascular New conception of pathophysiology in placental
functional study used a significantly larger sample size (for exam- ischemia and PH
ple n = 124) for human placenta [132]. Whether large or micro There are a lot of controversies and uncertainties about altered or
vessels, ACh showed no relaxation effects on 5-HT- or Ang-II- unchanged placental vascular reactivities, as well as changes of
increased vascular tension, regardless of normal or preeclamptic pivotal endogenous vasoactivators in the circulation and placenta
placenta. Meanwhile, L-NAME (an inhibitor of eNOS) did not in preeclampsia. On the whole, placental vessels are not what was
increase Ang-II-generated vasoconstrictions in either normal or previously assumed, and they behave very differently from non-
preeclamptic placental vessels. The concentrations of l-arginine, placental vessels. In pathophysiology, a local ischemia regarding
NO and NOS in placental tissue were significantly higher than vascular systems in an organ like the placenta usually occurs under
those in placental vessels. These data indicated that, unlike non- three vascular conditions: increased vascular resistance; reduced
placental vessels, vasorelaxation effects stimulated by endothelial vessel tone; and altered number or diameters in vessel branches or
NO systems in isolated placental vessels were very weak, and the terminals (Fig. 3). Although current theories on development of
NO-mediated placental vasodilatations were mainly from NO in PH put a finger on placental ischemia, which of the three vascular
placental tissue, not placental vessels. In addition, SNP did not conditions indicated above should be blamed for ischemia is
cause significant relaxation at the baseline level in various non- unclear and deserves extensive investigation in the future.
placental vessels from human, sheep or rats, whereas it produced a Despite the concerns mentioned above, recent studies with
significant drop from baseline tension in human and sheep pla- increased human sample size and additional animal models
cental vessels, whether in small or large vessels. Compared with showed an interesting physiological fact that Ang-II-mediated
normal pregnancy, SNP-induced vascular relaxation was signifi- vasocontractions in placental vessels are more dominant than
cantly weaker in preeclamptic placental vessels. Moreover, there nonplacental vessels in maintaining vascular tone, and Ang-II-
were no differences in NO precursors and products, as well as NO mediated placental vascular tension was reduced in preeclampsia
enzymes, between normal and preeclamptic placental tissue. [22], which is one of the three vascular conditions mentioned
Compared with normal pregnancy, cGMP production and sGC above that induces ischemia. The reduced placental vessel tone
activity were significantly decreased in preeclamptic placental sends signals out (Ang-II-mediated vasotension was too weak,
vessels, revealing that the cGMP/sGC pathway in placental VSMCs probably to be ‘wrongly’ translated into Ang II was not enough),
was injured in preeclampsia. Notably, NO is undoubtedly an then the pregnant woman and placenta produce more Ang II as a
important player in placental vascular relaxation, although NO response after receiving the ‘wrong’ signals, causing PH in preg-
is not mainly from placental vascular endothelium as previously nant women (Fig. 2). This can also can explain why some pre-
often thought, probably as a result of misusing knowledge regard- eclamptic women had a higher level of Ang II.
ing NO from nonplacental vessel studies. In fact, some previous Another pathophysiological question regarding endothelial
experiments on genes or molecules in the placenta were designed dysfunction in PH is getting clearer owing to recent progress.
Placental vascular Placental vascular

functional changes anatomy changes
Increased Decreased Vessel remodeling

vascular tone vascular tone
Vessel Reduced number of

collapse vessel branches
Vasospasm Placental poor perfusion Reduced

vessel
diameters
Placental ischemia
FIGURE 3
Placental ischemia should be based on one or more of the ‘three conditions’: increased vascular tone; decreased vascular tone; vascular remodeling.
One of the popular current theories on development of PH is pathophysiology of PH remain unclear. However, recent progress
endothelial dysfunction. There is no doubt that maternal endo- has been made in providing new and interesting evidence that
thelial dysfunction should be considered in development of PH, placental vascular physiology could be different from nonpla-
whereas many previous studies on placental endothelial molecules cental ones, especially for actions of ACh and Ang II [22,132].
demonstrated that placental endothelial dysfunction was also Placental ischemia could be produced by reduced vascular ten-
considered as the mechanism for development of PH [5,157]. In sion in response to certain vessel stimulators. Future investiga-
addition, if endothelial dysfunction occurs in general vascular tions would still focus on more evidence regarding placental

systems in pregnant mothers, there are no reasons why the pla- ischemia indicated in Fig. 1 as the real pathophysiology for
cental endothelium should be intact without any damage. Nota- development of PH. If this could be finally and firmly confirmed,
bly, NO-mediated vascular regulations are major endothelial pathophysiology for why and how placental ischemia was devel-
functions in nonplacental vessels. Recent progress in a study of oped should be a major concern. To understand this, special
vascular NO in the placenta has been made demonstrating that physiology of the placental vascular systems should be properly
ACh showed no classic NO-mediated vasodilation in human and and fully investigated. For example, physiological actions of HA
sheep placental blood vessels, whereas exogenous NO donor SNP and ET-1 on nonplacental vessels are understood; however,
could reliably reduce vascular basal tension [132]. This means: (i) knowledge about their effects on placental vessels is still very
the placental vascular endothelial NO system has limited roles in limited. Finally, only when the real pathophysiology of placental
vasodilation; (ii) exogenous NO outside of placental vessels is a vessels in development of PH is relatively clear will molecular
strong activator for vasorelaxation by acting on VSMCs in the experiments on the placenta designed to target related genes and
placenta. molecules seem more reasonable. In light of this, precision
medicine aiming at certain genes or molecules targeting certain
Concluding remarks and future perspectives symptoms or diseases requires the precise pathophysiology to be
As indicated above, two major functions of the placenta are known.
circulation and release of many various biofactors. This article
has focused on placental circulation and vessels. Table 1 shows Conflicts of interest
limited experiments and human samples as well as discordant The authors have no conflicts of interest to declare.
results in previous reports on physiology and pathophysiology in
placental vessels. In the analysis of possible causes for the discor- Acknowledgments
dancy, this review noted three causes: (i) sample size was gener- Supported in part by: National Nature & Science Foundation of
ally too small owing to huge variation in human subjects; (ii) lack China (81320108006, 81771592, 81570960, 81401244 and
of animal models in the study of placental vascular functions and 81500322); Natural Science Foundation of Jiangsu Province (Grant
dysfunctions linked to preeclampsia; (iii) even for those limited no. BK20140292); Suzhou Natural Science Foundation (Grant no.
functional placental vessel studies reported, many were per- SYS201451); and the Jiangsu Province’s Key Discipline (Fetal
formed 20 years ago. To determine sensitivity in tiny blood Medicine). The authors would like to apologize that this review
vessels, equipment sensitivity and accuracy is crucial. The cannot include all interesting and important work and
machines today are better than those of 20 years ago. As a result, publications regarding the etiology underlying placental ischemia
it is not strange that real physiology of placental vessels and real in preeclampsia owing to space constraints.
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What is precise pathophysiology in

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Genetic or immuno-dysfunction, etc.

Placental poor perfusion

Chemicals or molecules released into circulation

Maternal blood pressure

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Placental vascular bed Vascular reactivity of endogenous vasoactivators in

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Placental vascular Placental vascular

Increased Decreased Vessel remodeling

Vessel Reduced number of

Vasospasm Placental poor perfusion Reduced

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