preeclampsia , a pregnancy - complicated syndrome , is one of the leading causes of maternal and fetal morbidity and mortality .
this potentially dangerous condition affects approximately 27% of all pregnancies in the western world , but the incidence in developing countries can be greater [ 1 , 2 ] .
preeclampsia is a maternal systemic symptom of late second or third trimester of pregnancy , characterized by hypertension , proteinuria , fetal intrauterine growth restriction , and other maternal abnormity . in the worst cases
now , except for induced delivery , there is no effective treatment to cure it .
risk factors involved in preeclampsia have been increasingly identified ( table 1 ) , and emergence of any risk factor may cause a woman to develop preeclampsia . however , exact pathogenesis of this disorder remains uncertain since numerous research into the etiology of preeclampsia did not progress significantly .
understanding the detailed mechanism underlying preeclampsia will help to develop novel prophylactic and therapeutic interventions for this condition .
the current understanding about preeclampsia is that it appears to develop in a two - stage progress , with a preclinical initial stage which has an abnormal placenta , followed by a second stage during which release of soluble factors from hypoxic placenta leads to various observed maternal conditions , including hypertension , proteinuria , and generalized damage to the maternal organ .
preeclampsia is commonly considered to result from the presence of a poor placenta since the only effective cure of the clinical syndrome is delivery of the placenta .
placentation occurs from weeks 6 to 18 of gestation , during which extravillous cytotrophoblast invasion is required for extensive remodeling of maternal spiral arteries . in preeclampsia , placenta is extremely shallow because of inadequate trophoblast invasion and deficient remodeling of spiral arteries [ 5 , 6 ] .
implantation failure of placenta predisposes it to hypoxia and oxidative stress , thus resulting in a maternal systemic inflammatory response characterized by enhanced expression of inflammatory mediators .
it was found that dysfunctional placenta can release adverse factors into the maternal circulation , causing the clinical features of this condition .
these factors include some hormones or chemical substances , such as sflt1 ( soluble fms - like tyrosine kinase 1 ) , at1-aa ( angiotensin ii at1 receptor auto - antibody ) , and cardiac glycosides ( marinobufagenin , mbg ) . among these
, sflt1 can cause endothelial dysfunction in the maternal blood vessels by binding vascular endothelial growth factors and placental growth factor ; at1-aa can react with the at1 receptor in a stimulatory fashion similar to angiotensin ii signalling , which could contribute to maternal hypertension ; mbg , involved in the pathogenesis of preeclampsia , has been demonstrated to cause hypertension , proteinuria , and intrauterine growth restriction in the rat model of preeclampsia .
augmented release of these factors secondary to the original poor placenta will eventually lead to damage of the endothelium , metabolism dysfunction , and inflammation as well as other typical symptoms .  
then , what is the exact mechanism leading to deficient trophoblast invasion and further poor placenta ?
immune responses and maternal endocrine system can be considered to be two main elements involved in the development of placenta . there is evidence suggesting that shallow placenta is thought to stem from the lack of immune tolerance to pater - derived fetal antigens .
initial maternal rejection to the fetoplacenta may be the main reason for inadequate spiral arteries remodeling in preeclampsia . during the normal pregnancy , maternal innate immune response
th1/th2 activity balance is strongly shifted toward th2 activity to maintain the normal fetomaternal interaction .
many have found that maternal t cell can not recognize fetal human lymphocyte antigens ( hlas ) rightly and decidua nk cell has an unusual phenotype in preeclampsia .
moreover , another important difference found between normal pregnancy and preeclampsia is the shift of th1/th2 balance toward th1 responses .
in addition to immune maladaptation , it is also found that maternal endocrine system is perturbed in preeclampsia . in normal pregnancy ,
components of renin - angiotensin - aldosterone system , including renin , angiotensin , and aldosterone , are increased , while these hormones are suppressed in preeclampsia .
a recent report found that activation of mineralocorticoid receptor in trophoblast by maternal aldosterone appears to be required for trophoblast proliferation and placenta development .
additionally , other pregnancy - related hormones also make great contribution to favourable pregnancy outcome . for example , progesterone plays a dominant role in maintaining uterine quiescence and modulating fetomaternal immune response locally , while estrogen appears also to be a potent immunomodulator in pregnancy - associated immune function .
aberration in these hormones level may disrupt homoeostasis of placenta development , thus causing the onset of preeclampsia eventually .
overall , abnormal change in immune responses and maternal endocrine system throughout pregnancy may be one explanation for preeclampsia ( figure 1 ) .  
following extensive research into placentation , recent advances have identified emerging key players relevant to placenta establishment , including renin - angiotensin system ( ras ) , 1 , 25-dihydroxyvitamin d ( 1,25(oh)2d3 ) , and lipoxin a4 .
evidence indicates that aberration in them may disrupt placenta development , contributing to adverse pregnancy outcome , such as preeclampsia ( described subsequently ) .
v - atpase , another key molecule in placentation , is closely associated with all of them . during normal pregnancy ,
ras , 1,25(oh)2d3 , and lipoxin a4 may work independently , in parallel or jointly on the central molecule , v - atpase , while v - atpase also affects them at the same time .
therefore , the intriguing molecule v - atpase may represent a key link between various causes of preeclampsia . in the following
the present review will focus on some new findings about interaction between v - atpase and ras , 1,25(oh)2d3 and lipoxin a4 in pregnancy , which will provide new insights into the molecular mechanisms underlying preeclampsia .
the acidity regulation of intracellular and extracellular environment is crucial for a variety of biological processes , including acidity homeostasis , membrane trafficking , protein degradation , and sperm maturation .
central to this regulation is the vacuolar atpase ( v - atpase ) , which is a large multisubunit complex functioning as an atp - driven proton pump .
v - atpase is of significant importance in basic physiological processes , and it has been implicated in a number of human diseases , such as renal disease , tumour metastasis , and bone disease .
v - atpase is composed of two large domains , v0 and v1 . the v0 domain is a 260  kda membrane - embedded complex that contains six different subunits ( a , d , e , c , c , and c ) and functions as a proton - translocation domain , whereas the v1 domain is a 650  kda cytoplasmic complex that contains eight different subunits ( a , b , c , d , e , f , g , and h ) and functions as an atp - hydrolytic domain .
it is the structural complexity of v - atpase that makes it an important player in various physiological functions .
many of v - atpase subunits have multiple isoforms , and so specific v - atpase can be composed of different combinations of these subunit isoforms .  
v - atpase , mediating various physiological processes and cellular homeostasis , may be closely involved in different stages of reproduction .
in fact , there are many reports demonstrating that v - atpase has an important role in all aspects of mammalian reproduction , such as spermatogenesis , fertilization , embryonic implantation , and embryo development . on one hand ,
the acidic microenvironment regulated by v - atpase is essential for embryonic development following embryonic implantation . on the other hand ,
different v - atpase has specific tissue distribution in reproduction system and exerts differential crucial function . among all of the v - atpase subunits , subunit  a 
is involved in acrosomal reaction of sperm and embryonic implantation , both of which provide vital foundation for successful pregnancy . subunit 
a  is a large membrane - spanning protein with a hydrophilic cytoplasmic n - terminal domain and a nine - transmembrane c - terminal domain , and it contains the information necessary to target the v - atpase to different cellular destinations and is responsible for proton transport into the lumen of intracellular vesicles or across membranes .
( a1 , a2 , a3 , and a4 ) , which exhibit diverse tissue distribution and subcellular location .
( atp6v0a2 , referred to as a2v - atpase ) can be detected in the epididymis , kidney , lung , thymus , spleen , and placenta .
recently , increasing evidence indicates the crucial role of a2v - atpase in placental immune modulation associated with pregnancy . in early pregnancy
, many important cytokines secreted by placenta trophoblast cells and immune cells in decidua play a key role in embryonic implantation and fetomaternal immune tolerance .
interestingly , it is reported that a2v - atpase is important in controlling the expression of these essential cytokines .
thus , the normal expression and localization of a2v - atpase in fetoplacental unit is essential for pregnancy .
have reported that placental a2v - atpase expression is a link between multiple causes of spontaneous abortion in mice , and dysfunction of a2v - atpase in early pregnancy has been associated not only with spontaneous abortion but also with preeclampsia and fetal growth restriction .
another interesting study found that nox2/nadph oxidase regulates antigen crosspresentation in adaptive immunity through changing phagosome lumen ph , whereas the effect of nox2/nadph oxidase on phagosomal ph is antagonized by v - atpase , which may represent a novel mechanism responsible for the maintenance of immune tolerance .
taken together , these indicate the importance of v - atpase in maintaining reproduction process and placentation and modulating fetomaternal immune tolerance in pregnancy , whereas defective v - atpase may increase the risk of causing a poor placenta and inducing preeclampsia ( figure 2 ) .
the circulating renin - angiotensin system ( ras ) is an endocrine hormone system that plays a key role in regulating blood pressure and systemic electrolyte balance .
apart from systemic circulating ras , local ras is present in many tissues or organs , such as brain , heart , ovary , and placenta , and one of the major extrarenal ras during pregnancy is the placental ras . in pregnancy ,
the circulating ras maintains maternal electrolyte balance and blood pressure homoeostasis , facilitating expanding blood supply for fetus , while the placental ras has indispensable role in the uteroplacental unit .
components of placental ras have been confirmed to be involved in many molecular events of placental establishment .
a recent review reported that placental cytotrophoblast is rich in at1 receptor , and ang ii - at1 receptor signaling regulates multiple genes associated with normal trophoblast invasion , such as plasminogen activator inhibitor-1 ( pai-1 ) , such as soluble fms - like tyrosine receptor-1 ( sflt-1 ) and soluble endoglin ( s - eng ) .
additionally , ang ii signaling also activates nf - kappa b and stimulates the synthesis of reduced nicotinamide - adenine dinucleotide phosphate ( nadph ) oxidase by trophoblast .
moreover , it has been demonstrated by a recent study that activation of mineralocorticoid receptor in placental trophoblast by maternal aldosterone appears to be required for trophoblast growth and normal fetoplacental function .
therefore , in response to pregnancy , both systemic ras and placental ras need to be adapted to sustain a healthy pregnancy .  
, there is an increase in almost all the components of maternal ras , including renin , angiotensin , and aldosterone , but these hormones are suppressed in preeclampsia .
however , the changes happening in the components of uteroplacental ras are different from those observed in circulating ras .
recent studies demonstrated that upregulation of the at1 receptor expression , increase in renin level , and enhancement of ang ii production   occur in uteroplacental unit of preeclamptic women .
so , the expression profile of both systemic ras and placental ras in preeclampsia differs greatly from that of healthy uncomplicated pregnancy . additionally , there is a growing body of reports indicating the presence of the angiotensin ii type i receptor agonistic autoantibody ( at1-aa ) in preeclamptic women , and this autoantibody through at1 receptor signaling can result in dysregulation of the ras , then leading to clinical features of preeclampsia .
all abnormalities in both systemic ras and placental ras can cause poor placentation and preeclampsia .
there is accumulating evidence suggesting that components of ras are interrelated to v - atpase and are essential for regulating v - atpase activity .
the ( pro)renin receptor ( ( p)rr ) , encoded in atp6ap2 , plays a key role in activation of the local ras , while a truncated form of ( p)rr , termed m8.9 , was found to be associated with the v - atpase assembly and function , implicating a novel role of ( p)rr in v - atpase activity .
recently , another interesting report indicated that ( p)rr functions as an adaptor between wnt receptor and v - atpase , which is required for mediating wnt signaling .
it was found that angiotensin ii has profound effects on h transport and urinary acidification in kidney , mainly through its regulation on v - atpase activity , and it has also been confirmed to stimulate vacuolar h - atpase activity in renal acid - secretory intercalated cells from the outer medullary collecting duct .
not long before , a report showed that aldosterone may participate in the regulation of v - atpase activity in acid - secretory intercalated cells through rapid nongenomic stimulatory action and contribute to urinary acidification . meanwhile , another study , prior to this review , described that aldosterone has both genomic and nongenomic stimulatory effects on v - atpase in proximal s3 segments .
considering the content described earlier , it is reasonable that uteroplacental v - atpase function is a key link between ras and placentation .
therefore , any aberration in interaction between ras and v - atpase may induce preeclampsia by interfering various processes in placent development .
1,25-dihydroxyvitamin d ( 1,25(oh)2d3 ) , the active form of vitamin d , has long been considered to be a leading molecule in calcium and bone homeostasis . however , in the past years , it was found that vitamin d receptor ( vdr ) is present in most tissues and many tissues contain the 1,25(oh)2d3 synthase , 25(oh)d3 - 1-hydroxylase [ 31 , 32 ] , which makes us begin to be aware of multiple nonclassic actions of 1,25(oh)2d3 .
in fact , advances have shown that 1,25(oh)2d3 deficiency may increase the risk of developing a wide range of chronic diseases , including cancer , autoimmune disease , infectious disease , and cardiovascular disease . through binding to the vdr
, 1,25(oh)2d3 can generate a wide array of favorable nonclassic biological responses that are different from its classic actions in maintaining bone and calcium homeostasis , whereas these nonclassic actions are mainly linked to its regulation of cell proliferation , cell differentiation , and immune responses .
it is worth emphasizing that some of nonclassic biological effects of 1,25(oh)2d3 have been suggested to participate in modulation of embryo implantation , fetomaternal immune tolerance , and placental antimicrobial and anti - inflammatory responses .
therefore , 1,25(oh)2d3 deficiency in pregnancy may not only impair maternal and fetal bone health , but also cause various adverse pregnancy outcomes such as preterm birth , fetal intrauterine growth restriction , and preeclampsia .
al demonstrated that the level of 1,25(oh)2d3 in both maternal circulation and umbilical cord compartment is low in preeclampsia .
furthermore , expression and activity of 25-hydroxyvitamin d-1-hydroxylase has been confirmed to be significantly restricted in cultures of placental syncytiotrophoblast cells from preeclamptic pregnancy .
typical feature of preeclampsia is maternal systemic inflammatory response , characterized by upregulation of proinflammatory mediators in both uteroplacental unit and peripheral circulation .
in fact , as described previously , the systemic inflammatory response in preeclampsia is thought to stem from initial disorder of fetomaternal immune tolerance .
vitamin d , particularly 1,25(oh)2d3 , has received particular attention in recent years as it has been shown to have important effect on both innate and adaptive immune systems .
moreover , 1,25(oh)2d3 has been demonstrated to be essential for modulating tissue - specific immune responses and preventing chronic inflammation and autoimmunity .
increasingly , the immunomodulation of 1,25(oh)2d3 has been proposed as a key link between vitamin d and pregnancy .
in addition to be mainly synthesized in the kidney , 1,25(oh)2d3 can also be locally produced by immune cells , such as macrophage , dendritic cell , activated t cell , and probably b cell . in autocrine or paracrine manner ,
the local produced 1,25(oh)2d3 can exert a marked inhibitory effect on adaptive immune responses , promoting humoral th2 responses whilst suppressing cellular th1 responses [ 33 , 36 ] .
for example , 1,25(oh)2d3 is able to inhibit the differentiation , maturation , and immunostimulatory capacity of dcs by decreasing the expression of mhc class ii molecule , cd40 , cd80 , and cd86 .
a recent report by saito speculated that imbalance between regulatory t cell and th17 cell differentiation may explain pathogenesis of preeclampsia , which provides new light on pathophysiology of preeclampsia .
interestingly , 1,25(oh)2d3 has been confirmed to enhance tolerogenic immunity by inducing immunosuppressive treg , while proinflammatory th17 cell is suppressed by 1,25(oh)2d3 . in summary , maternal vitamin d level may influence pregnancy outcome through a variety of potential mechanisms , and impaired vitamin d status may lead to preeclampsia .  
indeed , a recent study demonstrated that in the presence of vitamin d , human osteoclasts express elevated v - atpase levels .
meanwhile , this work also described that 1,25(oh)2d3 can upregulate the activity of v - atpase complex .
although the study did not study the case in pregnancy , it will imply us that 1,25(oh)2d3 may have an important effect on uteroplacental v - atpase activity .
moreover , the ability of 1,25(oh)2d3 to regulate secretion of pregnancy - related hormones may explain its role in mediating v - atpase activity .
1,25(oh)2d3 has been confirmed to be an important player in the upregulation of estrogen biosynthesis , and the previous description has also revealed that v - atpase expression is estrogen dependent , which makes it reasonable to speculate that 1,25(oh)2d3 can act on v - atpase indirectly by influencing hormones level .
recently , a significative review suggested that autophagy is a general basis for the multiple health - promoting effects of vitamin d .
autophagy , depending on lysosomal self - digestion machinery , is an evolutionarily conserved self - catabolism process that is essential for cell growth , development , and homeostasis . to a great extent ,
v - atpase is vital for autophagy since v - atpase is of great importance for lysosomal function .
thus , coupled with v - atpase , 1,25(oh)2d3 could induce and activate autophagy , protecting human against many diseases .
autophagy is induced by several forms of cell stress including hypoxia , infection , and starvation .
if autophagy could not be initiated properly , disturbance in autophagy will result in a wide range of disorder . in the case of preeclampsia , abnormal placentation in early pregnancy predisposes placenta to ischemia , hypoxia , and oxidative stress , which accumulates large numbers of apoptotic trophoblast cells at uteroplacental interface .
if not treated through cell autophagy , the apoptotic trophoblast cells may impair further placenta development seriously and induce onset of preeclampsia .
thus , maternal vitamin d deficiency may trigger preeclampsia through affecting v - atpase activity , which seems to represent a general and basic pathogenesis of preeclampsia .
lipoxin , the  stop signal  for inflammation , is the first mediator recognized to have dual anti - inflammatory and proresolution activities . in mammals ,
lipoxin a4 , mainly depending on transcellular biosynthesis in the inflammation microenvironment , is derived from arachidonic acid by the sequential action of lipoxygenase ( lox ) .
this pattern of biosynthesis involves the initiation of arachidonic acid oxygenation by 5-lox in leukocytes , and then the intermediate leukotriene a4 is converted into lipoxin a4 by 12-lox in platelets .
interestingly , our previous results indicated that platelet - derived microparticles containing 12-lox can be transferred to leukotriene - producing mast cells , which represents a new pathway for lipoxin a4 biosynthesis in vivo .
lipoxin a4 can act on many cell types including blood cell , neural cell , and stromal cell .
lipoxin a4 displays selective regulation for leukocyte responses and trafficking in vivo through activating its specific receptor , alxr .
for example , in neutrophils , lipoxin a4-alxr interaction blocks neutrophil migration and infiltration into sites of inflammation .
by contrast , in monocytes , lxa4-alxr interaction stimulates monocyte recruitment and the phagocytosis of apoptotic neutrophils .
recently , we found that lipoxin a4 can suppress hepatocellular carcinoma via remodeling tumor microenvironment .
moreover , we found that alxr ( also termed fpr2 ) has an appreciable pleiotropic regulator role in macrophage polarization , and lxa4-induced m2a+m2c - like macrophage phenotype showed antitumorigenesis activities . taken together ,
all previous results show us the key role of lipoxin a4 as an essential modulator of immune response and homoeostasis .
inflammatory processes are central to a series of pregnancy events , while inflammation dysregulation is a typical feature of pregnant complications , such as preeclampsia and preterm .
normal pregnancy is characterised by a state of mild maternal systemic inflammation , which develops when pregnancy is progressing .
although preeclampsia is also associated with inflammatory response , it is an exaggerated maternal systemic inflammatory response .
in fact , this disorder is an extreme condition of a range of uncontrolled inflammatory responses induced by abnormal pregnancy .
lipoxin a4 , as an anti - inflammatory and proresolution mediator , will play an important role in human pregnancy .
in fact , level of lipoxin a4 in nonpregnant women is significantly lower than that in pregnant women , and circulating level of lipoxin a4 in pregnant women displayed a modest but significant increase throughout pregnancy .
thus , it is tempting to speculate that inadequate production of lipoxin a4 can lead to abnormality of placental immunomicroenviroment , increasing the risk of preeclampsia .
this has been confirmed by our results from clinical study that level of lipoxin a4 in preeclampsia is significantly lower than that in normal pregnancy .
additionally , our results from animal study demonstrated that lipoxin a4 could suppress the increased production of proinflammatory cytokines and alleviate the symptoms of preeclampsia in lps - induced rat model for human preeclampsia .
moreover , results from our previous study verified that lipoxin a4 can inhibit the enhanced il-1 production of monocytes from severe preeclampsia women .
recently , preliminary results from animal study indicated that lipoxin a4 may participate in the regulation of rat fetomaternal immune tolerance in early pregnancy
. therefore , lipoxin a4 , an endogenous anti - inflammatory and proresolution mediator , is a key player in terminating exaggerated inflammatory responses and restoring maternal systemic homoeostasis in pregnancy .  
the recent findings by russell et al . found that lipoxin a4 is a novel estrogen receptor modulator and exhibits estrogenic activity in vivo , revealing a previously unappreciated facet of various bioactions of this anti - inflammatory and pro - resolution mediator .
thus , lipoxin a4 may exert an important role in regulating the v - atpase expression , as v - atpase expression level is estrogen dependent , which has been mentioned earlier in this review .
in addition , v - atpase may also participate in the modulation of lipoxin a4 bioactions .
there is evidence implicating that v - atpase may get involved in the complex interaction between lipoxin a4 and its receptor in lipoxin a4-stimulated signal pathways .
reported that internalization and trafficking is critical for lxa4-stimulated phagocytosis in the resolution of inflammation .
transmembrane receptors internalization is of physiological importance , which is required for right signal transduction , proper dissociation of ligand from receptor , and receptor - mediated endocytosis .
although receptor internalization may occur in different ways , v - atpase - mediated intraendosomal pathway is the main endocytic trafficking machinery .
therefore , internalization and trafficking of lipoxin a4 receptor is likely to require the right assembly and activity of v - atpase in the endocytic complex of alxr internalization . if there is some defect in v - atpase , biological actions of lxa4 through alxr could be severely hindered . in summary
, lipoxin a4 may play an important role in modulating v - atpase activity during pregnancy while the key role of lipoxin a4 in fetomaternal immunoregulation also depends on normal v - atpase activity extensively .
based on the previous novel findings , a model of how placental v - atpase function can be a key link between multiple causes of preeclampsia is proposed ( figure 3 ) . on one hand ,
v - atpase is an essential modulator in regulating bioaction of ras , 1,25(oh)2d3 , and lipoxin a4 during pregnancy . on the other hand ,
key roles of ras , 1,25(oh)2d3 , and lipoxin a4 can be integrated into the v - atpase function in pregnancy .
right cross - talk between v - atpase and ras , 1,25(oh)2d3 , and lipoxin a4 can facilitate normal placentation and ensure successful pregnancy .
once disorder of v - atpase activity takes place at the fetomaternal interface , various bioactivity of ras , 1,25(oh)2d3 , and lipoxin a4 will come into great trouble , and vice versa .
any abnormality occurring at the interaction between v - atpase and ras , 1,25(oh)2d3 and lipoxin a4 could cause a defective placenta , which will be eventually involved in the progression of preeclampsia .
overall , the previous proposal not only suggests the importance of v - atpase in modulating essential components of maternal endocrine system ( ras ) and key molecules of fetomaternal immune interaction ( 1,25(oh)2d3 and lipoxin a4 ) , but also shows the key role of ras , 1,25(oh)2d3 , and lipoxin a4 in regulating v - atpase function .  
maternal endocrine system and immune responses have been long considered to be involved in normal placenta development .
the renin - angiotensin system is a typical endocrine hormone system that plays a key role in regulating placentation as well as maintaining normal pregnancy .
recently , the immunomodulation of vitamin d in pregnancy has been proposed as a key aspect of placental homoeostasis .
additionally , lipoxin a4 , as an anti - inflammatory and proresolution mediator , has been demonstrated to be vital in modulating fetomaternal immune tolerance during pregnancy . nevertheless , the complexity of various molecular events that occur at the fetomaternal interface in placenta development is far from being completely elucidated .
a series of molecular mechanisms needs to be coordinated for establishing a perfect placenta , while any deviation from this ordered course of molecular events may result in pregnancy complications , such as preeclampsia .
v - atpase , a key molecule in placentation , is beginning to be appreciated .
it is closely linked to renin - angiotensin system , 1,25(oh)2d3 , and lipoxin a4 .
further studies regarding v - atpase - related molecular mechanisms necessary for placentation are required , since clinical intervention to these potential dysregulated molecular events may eventually improve pregnancy outcome . 

clarify the potential role of placental v - atpase in preeclampsia.investigate the nature of interaction between v - atpase and ras , 1,25(oh)2d3 , and lipoxin a4 in normal pregnancy.investigate the causes of abnormal interaction between v - atpase and ras , 1,25(oh)2d3 , and lipoxin a4 in preeclampsia.understand the mechanisms of placental damage associated with defective v - atpase , ras , 1,25(oh)2d3 and lipoxin a4 in preeclampsia.study the effect of potential therapeutic agents on placental damage and maternal clinical signs of preeclampsia . 
 
investigate the nature of interaction between v - atpase and ras , 1,25(oh)2d3 , and lipoxin a4 in normal pregnancy .
investigate the causes of abnormal interaction between v - atpase and ras , 1,25(oh)2d3 , and lipoxin a4 in preeclampsia .
understand the mechanisms of placental damage associated with defective v - atpase , ras , 1,25(oh)2d3 and lipoxin a4 in preeclampsia .
study the effect of potential therapeutic agents on placental damage and maternal clinical signs of preeclampsia .
 preeclampsia , a relatively common pregnancy disorder , is one of the major causes of maternal and fetal morbidity and mortality . despite numerous research , 
 the etiology of this syndrome remains not well understood as the pathogenesis of preeclampsia is complex , involving interaction between genetic , immunologic , and environmental factors . 
 preeclampsia , originating in placenta abnormalities , is induced by the circulating factors derived from the abnormal placenta . 
 recent work has identified various molecular mechanisms related to placenta development , including renin - angiotensin system , 1 , 25-dihydroxyvitamin d , and lipoxin a4 . 
 interestingly , advances suggest that vacuolar atpase , a key molecule in placentation , is closely associated with them . therefore , this intriguing molecule may represent an important link between various causes of preeclampsia . here , we review that vacuolar atpase works as a key link between multiple causes of preeclampsia and discuss the potential molecular mechanisms . 
 the novel findings outlined in this review may provide promising explanations for the causation of preeclampsia and a rationale for future therapeutic interventions for this condition . 