Micro RNA: New aspect in pathobiology of preeclampsia?
The discovery of miRNA in 1993, by Ambros et al. has had a huge influence in pathogenesis theory; diagnosis and treatment approach to some diseases. Some scientifically proven theories have been proposed to seek the association of alterations of miRNA expression to incidences and severity of preeclampsia (PE). In this review we explore the result of such investigations that discuss the association of miRNA and PE along with the role of various mRNAs in PE pathogenesis.
Micro RNA: New aspect in pathobiology of preeclampsia?
, Mohd. Andalas
, Diky Mudhakir
, Natalia C. Pedroza
Saurabh V Laddha
, Jay R. Anand
Obstetrics and Gynecology Department, School of Medicine Syiah Kuala University, Banda Aceh, Indonesia
Schools of Pharmacy, Bandung Institute of Technology (ITB), Bandung, Indonesia
Viral Vector Core and Gene Therapy, Neuroscience Group, University Research Center, University of Antioquia,
G N Ramachandran Knowledge Center for Genome Informatics, Institute of Genomics and Integrative Biology (CSIR),
Mall Road, Delhi 110007, India
Department of Pharmacology, National Institute of Pharmaceutical Education and Research, Guwahati, India
Received 29 June 2011; accepted 28 September 2011
Available online 14 February 2012
Abstract The discovery of miRNA in 1993, by Ambros et al. has had a huge inﬂuence in pathogen-
esis theory; diagnosis and treatment approach to some diseases. Some scientiﬁcally proven theories
have been proposed to seek the association of alterations of miRNA expression to incidences and
severity of preeclampsia (PE). In this review we explore the result of such investigations that discuss
the association of miRNA and PE along with the role of various mRNAs in PE pathogenesis.
Ó 2012 Ain Shams University. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
2. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Corresponding author. Address: Obstetrics and Gynecology Depart-
ment, School of Medicine Syiah Kuala University, Jl. Tanoeh Abe,
Darussalam, Banda Aceh 23111, Indonesia. Tel.: +6285260850805.
E-mail address: email@example.com (H. Harapan).
1110-8630 Ó 2012 Ain Shams University. Production and hosting by
Elsevier B.V. All rights reserved.
Peer review under responsibility of Ain Shams University.
Production and hosting by Elsevier
The Egyptian Journal of Medical Human Genetics (2012) 13, 127–131
Ain Shams University
The Egyptian Journal of Medical Human Genetics
2.1. Biogenesis and mechanism action of miRNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
2.2. Molecular mechanisms of preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2.3. The role of miRNA in preeclampsia pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
4. Disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Preeclampsia (PE) is a disease of pregnancy characterized by
hypertension (deﬁned as systolic blood pressure P140 mm
Hg or diastolic blood pressure P90 mm Hg) and proteinuria
(300 mg or greater in a 24-h urine specimen and/or protein to
creatinine ratio of >0.30), developing after 20 weeks of gesta-
tion [1–3]. It has been estimated that PE affects 3–5% of preg-
nancies worldwide , recently, it has been reported that PE
complicates 3–8% of pregnancies . There is much evidence
shown that PE originates in the placenta [6,7] and thus the pla-
centa is believed as the central basis to the pathogenesis of PE
. But the molecular basis for placental dysregulation of these
pathogenic factors remains unknown. Many hypotheses have
emerged that attempt together a causal framework for the dis-
ease, causing PE to be named the ‘disease of theories’ .
MicroRNAs (miRNAs) are small, noncoding RNAs 22
nucleotides (nt) in length that regulate gene expression, with
important functions in the regulation of a variety of biologic
processes involved in development, cell differentiation, regula-
tion of cell cycle, metabolism and apoptosis [10–12]. Albeit only
1% of the genomic transcripts in mammalian cells encode miR-
NA , miRNAs are predicted to control the activity of more
than 60% of all protein-coding genes  . It has been estimated
that miRNAs regulate 30% of human genes [10,15].
MicroRNAs regulate mRNA, which encodes proteins that
modulate cellular functions, therefore, miRNAs play important
roles in physiological homeostasis in health and pathophysio-
logical derangement in disease . MicroRNAs are known to
have function in pathological process and prognosis of diseases
such as diabetes , neurodegenerative disorder , gastroin-
testinal diseases  and cancer and its resistance toward chemo-
therapy . It has been also proposed that the presence of single
nucleotide polymorphism (SNP) in the processing machinery
and target binding sites genes of miRNA affects cancer risk,
treatment efﬁcacy and patient prognosis . Certain miRNAs
are tissue-speciﬁc and the temporal expression of the tissue-spe-
ciﬁc miRNAs correlates closely with the speciﬁc physiological or
pathological status of the corresponding organs .
Research conducted by Pineles et al.  shows that PE is
associated with alterations in placental miRNA expression.
This research reported that miR-210 and -182 are expressed dif-
ferentially in the human placentas of patients with PE compared
with control subjects . In this review we will discuss the role
of miRNA as a new aspect in pathophysiology of PE.
2.1. Biogenesis and mechanism action of miRNA
The ﬁrst report on miRNA was presented in 1993 by Ambros
et al. who described a 22-nucleotide RNA in Caenorhabditis
elegans encoded by the lin-4 gene, which can bind to the lin-
14 transcript and interfere with its expression . Functional
studies indicate that miRNAs participate in the regulation of
almost every cellular process investigated so far and that
changes in their expression are associated with many human
MicroRNAs are processed from RNA polymerase II (RNA-
PII)-speciﬁc transcripts of independent genes or from introns of
protein-coding genes . These initial miRNA precursors,
known as pri-miRNAs, are processed into 70 nt hairpin struc-
tures known as pre-miRNAs – in the nucleus – by a nuclear en-
zyme complex known as the microprocessor that contains an
endoribonuclease – Drosha – and a double-stranded RNA bind-
ing protein – DiGeorge syndrome critical region 8 (DGCR8).
This process called as Drosha–DGCR8 step [22,24]. Drosha is
an RNase III enzyme which contains two RNase domains which
cleave the 5
ends, releasing the pre-miRNA . Some
pre-miRNAs are produced from very short introns (mirtrons)
that bypass the Drosha–DGCR8 step .
The pre-miRNA is exported from the nucleus to the
cytoplasm by Exportin-5 (XPO5) . In the cytoplasm, the
pre-miRNA is further cleaved by another RNase III enzyme –
Dicer, which removes the loop to yield the 22 nucleotide miR-
NA duplex . After being unwound by a helicase, one strand
of miRNA is destined to be the mature miRNA called as guide
strand and the complementary strand – called as passenger
strand or miRNA*– is rapidly degraded . The thermody-
namic stability of the miRNA duplex termini and the identity
of the nucleotides in the 3
overhang determine which strands
act as the guide strand . Then the guide strand is incorpo-
rated into a miRNA-induced silencing complex (miRISC)
Guided by the sequence complementarity between the small
RNA and the target mRNA, miRNA–RISC-mediated gene
inhibition is commonly divided into three processes: (a) site-
speciﬁc cleavage, (b) enhanced mRNA degradation and (c)
translational inhibition .
The miRISC–mRNA interaction can lead to several modes
of direct and indirect on translational repression . Direct
on translational repression involved: (a). Initiation block: The
miRISC inhibits translation initiation by interfering with
eIF4F-cap recognition and 40S small ribosomal subunit recruit-
ment or by antagonizing 60S subunit joining and preventing
80S ribosomal complex formation. (b) Postinitiation block: pre-
mature ribosomal drop-off, the 40S/60S ribosomes are dissoci-
ated from mRNA, stalled or slowed elongation, the 40S/60S
ribosomes are prohibited from joining during the elongation
process or facilitating proteolysis of nascent polypeptides
[13,25,28]. The indirect on translational repression occurs via
mRNA deadenylation and degradation [13,28]. Deadenylation
of mRNAs is mediated by glycine–tryptophan protein of
182 kDa (GW182) proteins – the components of miRISC,
poly(A)-binding protein (PABP), and Argonaute (AGO) pro-
128 H. Harapan et al.
tein [22,25,27]. Argonaute (AGO) proteins are core components
of the miRISC which are directly associated with miRNAs .
Then this molecule will interacts with the CCR4/CAF1 deaden-
ylase complex to facilitate deadenylation of the poly(A) tail
[22,25]. Following deadenylation, the 5
-terminal cap is re-
moved by the decapping enzyme – decapping DCP1-DCP2
complex . Endonucleolytic cleavage and mRNA degrada-
tion that miRNA-mediated by AGO2 [22,29].
2.2. Molecular mechanisms of preeclampsia
Angiogenic factors such as placental growth factor (PlGF) and
vascular endothelial growth factor (VEGF) and their receptors
Flt1 [also known as vascular endothelial growth factor receptor
1 (VEGFR-1)], VEGFR-2, Tie-1, and Tie-2, are essential for
normal placental vascular development . Alterations in the
regulation and signaling of angiogenic pathways in early gesta-
tion contribute to the inadequate cytotrophoblast invasion seen
in PE . Additionally, perturbation of the renin–aldosterone–
angiotensin II axis, excessive oxidative stress, inﬂammation,
immune maladaptation, and genetic susceptibility may all con-
tribute to the pathogenesis of PE .
Several placentally derived ‘‘toxins’’ were suggested, includ-
ing cytokines, anti-angiogenic factors, syncytiotrophoblast
microparticles (STBM), and formed blood products activated
in the intervillus space .
The role of these anti-angiogenic factors such as soluble
fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng)
in early placental vascular development and in trophoblast
invasion is just the beginning to be explored in placental dys-
regulation. Hypoxia is likely to be an important regulator
. Oxidative stress was an attractive component as part of
the linkage . Reactive oxygen species could be generated
by the reduced perfusion of the placenta with the consequent
activation of monocytes and neutrophils passing through the
intervillus space. Oxidative stress would also stimulate the re-
lease of cytokines, antiangiogenic factors, microparticles and
other potential linkers .
Some factors such as genetic factors, oxidative stress, cate-
chol-O-methyltransferase (COMT) deﬁciency, hemoxygenase
deﬁciency and immunologic/inﬂammatory factors cause pla-
cental dysfunction which leads to angiogenic imbalance, in-
crease sFlt1 and sEng, decrease PlGF and VEGF [8,32,33].
sFlt1 and sEng levels have been shown to be elevated in the
serum of preeclamptic women, as compared to those of normal
pregnant women, weeks before the appearance of overt clinical
manifestations of the disease [34,35]. Compared to normo-ten-
sive controls, in patients with severe PE, free PlGF and VEGF
levels are signiﬁcantly declined [34,35] and sFlt1 levels are sig-
niﬁcantly elevated .
It is clear that the increase of sFlt1 expression associated
with decreased PlGF and VEGF signaling causes inadequate
placental vascular development [34,37,38]. These alterations
cause widespread endothelial dysfunction that results in hyper-
tension, proteinuria, and other systemic manifestations of pre-
2.3. The role of miRNA in preeclampsia pathogenesis
The ﬁrst research that linked miRNA and PE was conducted
by Pineles et al.  The study was performed to determine
whether PE and small-for-gestational age (SGA) are associ-
ated with alterations in placental miRNA expression. Thus
they evaluated placental miRNAs’ expression from patients
with PE, SGA, PE + SGA along with a control group. They
found that seven miRNAs (miR-210, miR-155, miR-181b,
, miR-200b, miR-154
, and miR-183) were signiﬁ-
cantly higher expressed between PE + SGA and the control
group. The expression of miR-182 and miR-210 was signiﬁ-
cantly higher in PE than in the control group. Based on Gene
Ontology (GO) analysis, miR-182 has a role to down-regulate
anti-apoptosis genes. They speculated that high expression of
miR-182 in PE may contribute to the increased apoptosis in
the placentas of patients with PE. The targets of both miR-
182 and miR-210 are enriched in immune processes, which
support the association between abnormal immune responses
and PE as descripted previously by Kim et al. . Beside that,
angiogenin and VEGF-b are potential targets of miR-182 and
, respectively . These molecules have a role in
angiogenesis. A study by Yang et al.  elucidates miRNA
essentiality, that in mice with deﬁcient miRNA, defective angi-
ogenesis is caused that leads to embryonic lethality.
A study with small sample in China found the expression of
miR-130a, miR-181a, miR-222, miR-16, miR-26b, miR-29b
and miR-195 in the placenta of severe PE women . The
other research reported that miR-16, miR-29b, miR-195,
miR-26b, miR-181a, miR-335 and miR-222 were signiﬁcantly
increased in placenta from women with severe PE . This re-
search revealed that some angiogenic growth factors were po-
tential targets of the altered miRNA, such as cysteine-rich 61
(CYR61), PlGF, VEGF-A which were targets of miR-222,
miR-335 and miR-195, respectively . It describes the role
of this angiogenics factors for the development of PE. It is well
known that the expressions of VEGF-A and VEGF receptor-1
are down-regulated in the cytotrophoblasts of PE placenta
[32,43]. Several articles reviewed by Lam et al.  provide suf-
ﬁcient evidence that PlGF is also dysregulated in serum or the
placental tissue of women with PE.
The research by Mo et al.  found that CYR61 is essen-
tial for placental development and vascular integrity. Gellhaus
et al.  found that CYR61 is signiﬁcantly decreased in PE
placenta. CYR61 is a secreted matrix protein expressed by
nearly all types of vascular cells and trophoblasts and impli-
cated in diverse cellular processes such as proliferation, migra-
tion, differentiation, and adhesion. It was found that the
expression of CYR61 in human placenta was signiﬁcantly low-
er than that of the normal control . Recently, a study re-
ported that overexpression of miR-155 contributes to PE
development by targeting and down-regulating angiogenic reg-
ulating factor CYR61 . It was also reported that CYR61
has been demonstrated to be one of the important early angio-
genic factors during pregnancy, this role is probably because
CYR61 can induce the expression of VEGF .
Poliseno et al.  found that overexpression of miR-221/
222 inhibits tube formation, migration, and wound healing
in response to stem cell factor in human umbilical endothelial
cells (HUVEC). This effect, arises because c-kit is a target of
miR-221/222. c-kit is a tyrosine kinase receptor for stem cell
factor and has been shown to promote survival, migration,
and capillary tube formation HUVEC .
The other study by Zhu et al.  was conducted in China
population. They investigated that 34 miRNAs were expressed
differentially in PE placentas, compared to normal placentas.
Micro RNA 129
Of these, 11 microRNAs were over-expressed, and 23 miRNAs
were under-expressed in PE placentas. miR-518b showed sig-
niﬁcant overexpression in severe PE vs control; miR-18a, -
363, and -542-3p were signiﬁcantly underexpressed in severe
PE vs control. miR-152 showed signiﬁcant overexpression in
mild PE vs control specimens and in severe PE vs control spec-
imens. miR-411 and miR-377 were under-expressed in mild PE
vs control specimens and in severe PE vs control. Zhu et al.
 also found that miR-210 was signiﬁcantly underexpressed
in mild PE vs the other two groups; while signiﬁcant overex-
pression was found in severe PE vs all other groups. In their
comments, they mention that the increase in miR-210 expres-
sion in sPE induced by the focal regions of ischemia/hypoxia
in placentas is the cause of poor placentation in PE pregnan-
cies, as a previous study showed that the expression of miR-
210 was increased on exposure to hypoxia . They specu-
lated the decrease of miR-210 in mPE to be a compensatory
mechanism in the pregnancies with mPE, but there is no sufﬁ-
Recently, Enquobahrie et al.  found that eight miR-
NAs were differentially expressed (miR-210 up-regulated
and 7 – miR-328, miR-584, miR-139-5p, miR-500, miR-
1247, miR-34C-5p and miR-1-down-regulated) among PE
cases compared with controls. These miRNAs target genes
that participate in organ/system development (cardiovascular
and reproductive systems), immunologic dysfunction, cell
adhesion, cell cycle, and signaling. In their comment consis-
tent with the other scientist, they stated that miR-210 plays
roles in endothelial cell response to hypoxia, formation of
capillary-like structures, vascular endothelial growth factor –
driven cell migration, cell differentiation, and survival, events
that are integral to PE pathogenesis. Enquobahrie et al. 
utilizing the results of previous study conducted by Ikeda
et al.  speculated that miR-1 inﬂuences risk of PE through
its effect on calcium signaling. They demonstrated that miR-1
inﬂuences calcium signaling through negative regulations of
the calmodulin-coding mRNAs, Mef2a and Gata4, mainly
in smooth muscle cells. It is believed that PE has associated
with abnormal calcium metabolism and related consequences
The association between PE and altered miRNA expression
suggests the possibility of a functional role for miRNA in this
disease. These different miRNAs may play an important role
in the pathogenesis of PE and may become diagnostic markers
and therapeutic target for PE.
In summary, we have shown that there are many scientiﬁc evi-
dences that have proven the fact that the differential placental
and plasma miRNA expression is associated with PE. Some re-
searches also identify novel candidate miRNAs (and pathways
they regulate) that may be of etiologic relevance in the patho-
genesis of PE. It provides novel targets for further investiga-
tion of the pathogenesis of PE and these differential
miRNAs may be potential markers for the diagnosis and pro-
vide a potential therapeutic target for PE. Further investiga-
tions on posttranscriptional regulation in PE to evaluate
biologic effects of identiﬁed miRNAs (including the conﬁrma-
tions of miRNA and target gene interactions) are needed.
4. Disclosure statement
There is no conﬂict of interest in writing of this manuscript.
 Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet
 Am. Coll. Obstet. Gynecol. Comm. Obstet. Pract. Diagnosis and
management of preeclampsia and eclampsia. Obstet Gynecol
 Report of the National High Blood Pressure Education Program
Working Group on High Blood Pressure in Pregnancy. Am J
Obstet Gynecol 2000;183:S1e22.
 WHO. 2005. World health report: Make every mother and child
count. Geneva: World Health Organization.
 Duley L. The global impact of pre-eclampsia and eclampsia.
Semin Perinatol 2009;33:130e7.
 Koga K, Osuga Y, Tajima T, Hirota Y, Igarashi T, Fujii T, Yano
T, Taketani Y. Elevated serum soluble fms-like tyrosine kinase 1
(sFlt1) level in women with hydatidiform mole. Fertil Steril
 Matsuo K, Kooshesh S, Dinc M, Sun CC, Kimura T, Baschat
AA. Late postpartum eclampsia: report of two cases managed by
uterine curettage and review of the literature. Am J Perinatol
 Young BC, Levine RJ, Karumanchi SA. Pathogenesis of Pre-
eclampsia. Annu Rev Pathol Mech Dis 2010;5:173–92.
 Cerdeira AS, Karumanchi SA. Biomarkers in Preeclampsia.
Biomarkers in Kidney Disease. Elsevier Inc.; 2010. p. 385–426.
 Garzon R, Calin GA, Croce CM. MicroRNAs in Cancer. Annu
Rev Med 2009;60:167–79.
 Bushati N, Cohen SM. MicroRNA functions. Annu Rev Cell Dev
 Kloosterman WP, Plasterk RHA. The diverse functions of
microRNAs in animal development and disease. Dev Cell
 Sun W, Li YSJ, Huang HD, Shyy J Y-J, Chien S. microRNA: a
master regulator of cellular processes for bioengineering systems.
Annu Rev Biomed Eng 2010;12:1–27.
 Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian
mRNAs are conserved targets of microRNAs. Genome Res
 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and
function. Cell 2004;116:281–97.
 Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X,
Macdonald PE, Pfeffer S, Tuschl T, Rajewsky N, Rorsman P,
Stoffel M. A pancreatic islet-speciﬁc microRNA regulates insulin
secretion. Nature 2004;432:226–30.
 Jin P, Alisch RS, Warren ST. RNA and microRNAs in fragile X
mental retardation. Nat Cell Biol 2004;6:1048–53.
 Pellish RS, Nasir A, Ramratnam B, Moss SF. Review article:
RNA interference – potential therapeutic applications for the
gastroenterologist. Aliment Pharmacol Ther 2008;27:715–23.
 Garofalo M, Croce CM. microRNAs: master regulators as
potential therapeutics in cancer. Annu Rev Pharmacol Toxicol
 Ryan BM, Robles AI, Harris CC. Genetic variation in microRNA
networks: the implications for cancer research. Nature Reviews
 Pineles BL, Romero R, Montenegro D, Tarca AL, Han YM, Kim
YM, Draghici S, Espinoza J, Kusanovic JP, Mittal P, Hassan SS,
Kim CJ. Distinct subsets of microRNAs are expressed differen-
tially in the human placentas of patients with preeclampsia. Am J
Obstet Gynecol 2007;196:261.e1–6.
130 H. Harapan et al.
 Krol J, Loedige I, Filipowicz W. The widespread regulation of
microRNA biogenesis, function and decay. Nat Rev Gene. 2010.
 Carthew RW, Sontheimer EJ. Origins and mechanisms of
miRNAs and siRNAs. Cell 2009;136:642–55.
 Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA
translation and stability by microRNAs. Annu. Rev. Biochem
 Fabian MR, Sundermeier TR, Sonenberg N. Understanding How
miRNAs Post-Transcriptionally Regulate Gene Expression. In:
Rhoads RE, editor. miRNA Regulation of the Translational
Machinery Progress in Molecular and Subcellular Biology 50.
Berlin Heidelberg: Springer-Verlag; 2010. p. 1–20.
 Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the
nuclear export of pre-microRNAs and short hairpin RNAs. Genes
 Gu S, Kay MA. How do miRNAs mediate translational repres-
sion? Silence 2010;1:11–5.
 Nilsen TW. Mechanisms of microRNA-mediated gene regulation
in animal cells. Trends in Genetics 2007;23:243–9.
 Ender C, Meister G. Argonaute proteins at a glance. Cell Sci
 Roberts JM, Hubel CA. The two stage model of preeclampsia:
variations on the theme. Placenta 2009;30(23):S32–7.
 Mellembakken JR, Aukrust P, Olafsen MK, Ueland T, Hestdal
K, Videm V. Activation of leukocytes during the uteroplacental
passage in preeclampsia. Hypertension 2002;39:155–60.
 Mutter WP, Karumanchi SA. Molecular mechanisms of pre-
eclampsia. Microvascular Research 2008;75:1–8.
 Maynard SE, Epstein FH, Karumanchi SA. Preeclampsia and
angiogenic imbalance. Annu Rev Med 2008;59:61–78.
 Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF,
Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM,
Sukhatme VP, Karumanchi SA. Circulating angiogenic factors
and the risk of preeclampsia. N Engl J Med 2004;350:672e83.
 Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai
BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA.
CPEP study group. Soluble endoglin and other circulating
antiangiogenic factors in preeclampsia. N Engl J Med 2006;355:
 Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C,
Bodnar LM, Crombleholme WR, Ness RB, Roberts JM, Hubel
CA. Soluble fms-like tyrosine kinase 1 is increased in preeclampsia
but not in normotensive pregnancies with small-for-gestational-
age neonates: relationship to circulating placental growth factor. J
Clin Endocrinol Metab 2005;90:4895–903.
 Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim
YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE,
Roberts D, D’Amore PA, Epstein FH, Sellke FW, Romero R,
Sukhatme VP, Letarte M, Karumanchi SA. Soluble endoglin
contributes to the pathogenesis of preeclampsia. Nat Med 2006;
 Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S,
Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH,
Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like
tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunc-
tion, hypertension, and proteinuria in preeclampsia. J Clin
 Kim YM, Romero R, Oh SY, Kim CJ, Kilburn BA, Armant R,
Nien JK, Gomez R, Mazor M, Saito S, Abrahams VM, Mor G.
Toll-like receptor 4: a potential link between ‘‘danger signals,’’ the
innate immune system, and preeclampsia? Am J Obstet Gynecol
 Yang WJ, Yang DD, Na S, Sandusky GE, Zhang Q, Zhao G.
Dicer is required for embryonic angiogenesis during mouse
development. J Biol Chem 2005;280:9330–5.
 Fei LP, Li HY, Sha H, Liu L, Li ZJ, Yi HY. The expression of
microRNA in placenca from severe preeclampsia patients.
Chinese Journal of Practical Gynecology and Obstetrics 2009;
 Hu Y, Li P, Hao S, Liu L, Zhao J, Hou Y. Differential expression
of microRNAs in the placentae of Chinese patients with severe
pre-eclampsia. Clin Chem Lab Med 2009;47(8):923–9.
 Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen
T, Alitalo K, Damsky C, Fisher SJ. Vascular endothelial growth
factor ligands and receptors that regulate human cytotrophoblast
survival are dysregulated in severe preeclampsia and hemolysis,
elevated liver enzymes, and low platelets syndrome. Am J Pathol
 Lam C, Lim KH, Karumanchi SA. Circulating angiogenic factors
in the pathogenesis and prediction of preeclampsia. Hypertension
 Mo FE, Muntean AG, Chen CC, Stolz DB, Watkins SC, Lau LF.
CYR61 (CCN1) is essential for placental development and
vascular integrity. Mol Cell Biol 2002;22:8709–20.
 Gellhaus A, Schmidt M, Dunk C, Lye SJ, Kimmig R, Winterh-
ager E. Decreased expression of the angiogenic regulators CYR61
(CCN1) and NOV (CCN3) in human placenta is associated with
pre-eclampsia. Mol Hum Reprod 2006;12:389–99.
 Zhang Y, Diao Z, Su L, Sun H, Li R, Cui H, Hu Y. MicroRNA-
155 contributes to preeclampsia by down-regulating CYR61. Am
J Obstet Gynecol 2010;202:466.e1–7.
 Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods
K, Mercatanti A, Hammond S, Rainaldi G. MicroRNAs mod-
ulate the angiogenic properties of HUVECs. Blood 2006;108:
 Matsui J, Wakabayashi T, Asada M, Yoshimatsu K, Okada M.
Stem cell factor/c-kit signaling promotes the survival, migration,
and capillary tube formation of human umbilical vein endothelial
cells. J Biol Chem 2004;279:18600–7.
 Zhu X-M, Han T, Sargent IL, Yin G-W, Yao Y-Q. Differential
expression proﬁle of microRNAs in human placentas from
preeclamptic pregnancies vs normal pregnancies. Am J Obstet
 Fasanaro P, D’Alessandra Y, Di Stefano V, Melchionna R,
Romani S, Pompilio G, Capogrossi MC, Martelli F. MicroRNA-
210 modulates endothelial cell response to hypoxia and inhibits
the receptor tyrosine-kinase ligand Ephrin-A3. J Biol Chem
 Enquobahrie DA, Abetew DF, Sorensen TK, Willoughby D,
Chidambaram K, Williams MA. Placental microRNA expression
in pregnancies complicated by preeclampsia. Am J Obstet
 Ikeda S, He A, Kong SW, Lu J, Bejar R, Bodyak N, Lee KH, Ma
Q, Kang PM, Golub TR, Pu WT. MicroRNA-1 negatively
regulates expression of the hypertrophy-associated calmodulin
and Mef2a genes. Mol Cell Biol 2009;29:2193–204.
 Thway TM, Shlykov SG, Day MC, Sanborn BM, Gilstrap 3rd
LC, Xia Y, Kellems RE. Antibodies from preeclamptic
patients stimulate increased intracellular Ca
through angiotensin receptor activation. Circulation 2004;110:
Micro RNA 131