Probable Factors Leading To Preeclampsia Biology Essay

Published: Last Edited:

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

Preeclampsia is a disease that occurs only in pregnant women. It is characterized by the onset of hypertension during pregnancy after 20 weeks of fetal gestation (Grill 2009). Symptoms of preeclampsia also include renal dysfunction which in turns causes proteinuria, edema in extremities, and HELLP syndrome. HELLP syndrome is a group of symptoms that includes hemolysis, elevated liver enzymes, and thrombocytopenia (Mutter 2008). Women most at risk for developing preeclampsia are those who are pregnant for the first time. These women are three times more likely to develop preeclampsia than women who have been pregnant before and did not develop preeclampsia. Multiple fetal pregnancies, where the woman is carrying twins or triplets, for example, also increase the risk of preeclampsia. Women that are obese, over the age of forty, or have a familial history of preeclampsia are also at higher risk (Duckitt 2005). Preeclampsia is also hypothesized to be associated with autoimmunity, so women who have a history of autoimmune disorders like multiple sclerosis or rheumatoid arthritis are believed to be at greater risk (Grill 2009).

Preeclampsia describes the extreme hypertensive episode before eclampsia. The woman becomes eclamptic once seizures begin. For decades the standard obstetric response was the administration of magnesium sulfate both to prevent the seizure and reduce the severity of the episode once seizing begins (Whitlin 1998). This practice treats the symptoms of the disease but no real drug option exists to treat the cause of preeclampsia, mostly because no one knows the exact cause. The best known treatment of severe preeclampsia is delivery of the placenta. The disease is almost always self-limiting but if the preeclampsia symptoms become severe enough delivery is the only option (Mutter 2008). Delivering the fetus and all the placental material prematurely can have very serious adverse effects on the newborn infant. When the severity of the symptoms require the abrupt delivery of the fetus, the fetus may not be developed enough to survive. Thus preeclampsia results in high infant morbidity and mortality (Whitlin 1998).

Preeclampsia is a disease in which the exact cause has remained elusive, but new research has made much progress toward determining its source. As well as identifying possible molecular markers to allow for better prediction of the disease prior to the onset of serious symptoms, the relationship between abnormalities in the placenta, inappropriate binding of the mineralcorticoid receptor, the role of adipokines, and a newly discovered autoantibody have begun to unravel this biological mystery.

Progesterone and the Mineralcorticoid Receptor

During pregnancy the plasma progesterone concentration is 100 times greater than its basal concentration (Geller 2000). One of the early theories as to the pathogenesis of preeclampsia was that excess progesterone would bind the aldosterone receptor, known as the mineralcorticoid receptor (MR). The hormone binding domain of steroid hormone receptors are highly homologous. The progesterone receptor and the MR in the kidney are very similar and only differ by 3 amino acid residues (Geller 2000). Aldosterone is a mineralcorticoid hormone that acts on the collecting ducts of the kidney to increase the reabsorption of sodium ions. The reabsorption of sodium ions then causes an increase in solute concentration of blood. The increased osmolarity causes the retention of more water. Increasing the blood volume directly increases blood pressure. If progesterone binds the MR and activates this sodium reabsorption inappropriately a pathogenic rise in blood pressure can be expected.

Research has been done that explores the allelic variation of the MR and the mutations that are most associated with increased risk of preeclampsia. An allele involved in making the MR has a single amino acid substitution at the 810 position that replaces a leucine with a serine. This mutation comprises the MRL810 allele for the MR. This mutated allele causes the creation of an extra Van der Waal interaction between the hormone binding domain of the MR and progesterone. This extra interaction helps stabilize the binding of progesterone to the MR. This same stabilization is not seen in aldosterone binding. Agonistic progesterone binding is then elevated in those women who express the protein receptor product of the mutated MR L810 allele (Geller 2000). This allele can then cause an increase in progesterone binding of the MR and contribute to the overall symptoms of preeclampsia.

Poor placental implantation

Figure 1. Diagram showing shallow trophoblast invasion in placenta compared to normal pregnancy (Moffett-King 2002). Another factor that can play a role in the development of preeclampsia is the implantation of the placenta. Placental implantation is becoming a key factor in determining the likelihood of future preeclampsia. Shallow placental implantation in the uterine wall can have serious effects on both the mother and the fetus during the entire pregnancy. The vascular remodeling of the spiral arteries in the uterus that will feed the growing fetus, initiated after placental implantation, is a vital first step in the development of preeclampsia according to the two stage model of preeclampsia development (Roberts 2009). The remodeling is done by invasion of trophoblasts and happens early in pregnancy. This angiogenesis in the placenta lays down the groundwork for the delivery of nutrients to the fetus for the duration of the pregnancy. If the invasion is too shallow as depicted in Figure 1 then the mother is at risk for developing preeclampsia. The resulting low perfusion of nutrients and oxygen to the fetus is hypothesized to cause the release of molecule(s) from the fetal-maternal interface that leads to the high blood pressure seen in preeclampsia. The theory is that the increase in blood pressure then allows more nutrients to make the journey through the placenta and umbilical cord to the growing fetus (Hanssens 1998). The exact molecule and signaling mechanism is a focus of future research.

Autoantibody agonistic binding of the AT1 receptor

Another theory for the development of preeclampsia attributes the clinical manifestations of the disease to the presence of a single auto-antibody. An auto-antibody is a protein made by the cells of the immune system and is released into the blood plasma and binds to our body tissues inappropriately. In the case of preeclampsia an auto-antibody binds to the angiotensin II (Ang II) receptor, AT1 (Wallukat 1999). The auto-antibody for the Ang II receptor is known as AT1-AA. In a 2009 study of preeclamptic women, 80% had detectable amounts of AT1-AA in the blood, compared to 20% of normotensive pregnant women (Herse 2009). The increased presence of AT1-AA in preeclamptic women has caused much research to be done on the effects of AT1-AA in pregnancy. The AT1-AA is able to bind the Ang II AT1 receptor with enough binding affinity to activate multiple intracellular signaling pathways associated with the hormone Ang II.

Ang II is a hormonal component in the renin-angiotensin system (RAS). The RAS is a multistep process that results in the active form of Ang II circulating in the blood. Ang II is potent vasoconstrictor that functions to maintain blood pressure homeostasis and control the fluid retention of the body via effects on the kidney (Celi 2008). The newly discovered AT1-AA elicits the same response as Ang II in its target cells. One of the effects of Ang II is to stimulate the release of aldosterone. Aldosterone, as previously stated causes the reabsorption of sodium ions and results in increased blood pressure. This inappropriate signaling by an aberrant auto-antibody can help to explain some of the pathology associated with preeclampsia.

AT1-AA causes excess release of sFlt 1

The AT1-AA has also been implicated in the clinical manifestation of preeclampsia via another route. The protein soluble fms-like tyrosine kinase 1 (sFlt 1) is an anti-angiogenic factor that is normally released in response to Ang II binding cells on the placenta late in pregnancy. This binding inhibits the formation of new blood vessels (Herse 2009). In preeclampsia, agonistic binding of the AT1 receptor by AT1-AA causes an abnormal spike in sFlt 1 in the blood which inhibits angiogenesis prematurely in pregnancy. Increased levels of sFlt 1 directly inhibit proper placental implantation and trophoblast invasion (Mutter 2008). The release of sFlt 1 is also induced by hypoxic conditions with increased carbon monoxide levels. This theory was supported by a study in which smokers, who have a higher plasma carbon monoxide, were at a lower risk for preeclampsia than women who use smokeless tobacco (England 2003). This finding was explained by the presence of the enzyme heme oxygenase-1. Heme oxygenase-1(HO-1) is an enzyme that directly inhibits the actions of sFlt 1and works best under conditions of high carbon monoxide (Cudmore 2007). The higher levels of active HO-1 caused a decrease in the antiangiogenic sFlt 1 and a decrease in clinical preeclampsia symptoms.

The release of sFlt 1 also works to inhibit the activity of placental growth factor (PGF). The circulating sFlt 1 will bind to PGF and neutralize it so the PGF molecule is unable to activate its receptor (Venkatesha 2006). PGF is a proangiogenic factor that helps with the formation and modeling of the newly formed placental blood vessels. The drop in PGF and rise in sFlt 1 is a candidate for a clinical marker that has the potential to be used to detect early-onset preeclampsia (Levine 2006).

AT1 as a cause of ischemic placenta via blood vessel occlusion

The auto-antibody has been implicated as a cause of the shallow trophoblast invasion as shown in Figure 1. Instead of preeclampsia developing after defective modeling of placental tissue by chance in mothers, the AT1-AA has been named as a possible causative agent of the ischemic placenta. AT1-AA acts to increase the plasma concentration of the protein plasminogen activator inhibitor-1 (PAI-1). The release of PAI-1 occurs normally via a signaling pathway typically attributed to angiotensin II. PAI-1 is a serine protease released by the trophoblast cells of the placenta and inhibits conversion of plasminogen to plasmin (Xia 2009). Plasmin is the active form of the enzyme that controls the fibronolytic process in the placenta (Swellam 2009). Fibrinolysis is the process of chopping up fibrin clots by multiple proteolytic cleavages. The fibrin clots can occlude blood vessels. Fibrinolysis allows for easier transportation of blood and nutrients through the arteries of the body. The increased concentration of PAI-1 can inhibit the fibrinolytic process by inhibiting of the conversion of plasminogen to plasmin. This reduction in plasmin concentration can then cause dysfunction in the endothelial wall and blood vessel narrowing. Narrowing the diameter of the blood vessels of the placenta would inhibit blood flow and create hypoxic conditions for the fetus. In response to the placental ischemia, blood pressure is further increased to boost the efficiency of nutrient delivery to the fetus. This would also contribute to the overall hypertension in preeclampsia (Wikström 2009). PAI-1 has been shown to be significantly increased in women with severe preeclampsia through analysis of the expelled placental tissue (Estellés 1998).

AT1-AA can also bind the Ang II receptor on vascular smooth muscle cells and activate the intracellular pathway involved in the transcription of the gene that makes the tissue factor (TF) protein (Dechend 2000). Tissue factor is a protein that stimulates fibrin coagulation. This causes excess fibrin deposition in the blood vessels of the placenta (Xia 2009). The formation of excess fibrin buildups in the vessels has an obvious link to the epidemiology of preeclampsia. Narrower blood vessels can inhibit blood flow and result in hypertension. The AT1-AA can then inhibit the fibrinolytic process to break through the excess fibrin clots and inappropriately stimulate the release of the protein responsible for forming the fibrin clots in the first place.

AT1 causes increase in soluble endoglin

Like sFlt 1 and PAI-1, the molecule soluble Endoglin (sEng) has been shown to be elevated in preeclamptic women (Chaiworapongsa 2010). This increase in plasma concentration of sEng is stimulated via agonistic AT1-AA binding of the endothelial cells that produce sEng (Zhou 2010). An increased level of sEng is a very powerful antiangiogenic factor that can severely inhibit proper placental implantation (Chaiworapongsa 2010). The cell surface endoglin molecule that is still attached to the cellular membrane is a coreceptor for transforming growth factor-β1 (TGF-β1). The soluble form of endoglin is then hypothesized to competitively inhibit the binding of TGF-β1 to its receptor. This decreases the binding of TGF-β1 from binding its receptor and inhibits vascular dilation via the enzyme endothelial nitric oxide synthase (eNOS) (Venkatesha 2006). The inhibition of eNOS causes increased rigidity of the blood vessels and makes them less able to respond appropriately to alleviate an increase in blood pressure.

Soluble Endoglin can also contribute to the pathogenesis of preeclampsia in a second way. Earlier in this paper a theory was presented that suggested shallow trophoblast invasion causes the release of an unknown molecule from the maternal-fetal interface that contributes to the pathogenesis of preeclampsia. The unknown molecule could be the bound endoglin coreceptor. In response to the reduction in blood flow to the placenta, endothelial cells synthesize more endoglin to transduce the signal from TGF-β1 to activate eNOS. Greater concentration of eNOS causes an increase in blood vessel diameter and allows for easier movement of nutrients through the placenta and umbilical cord into the fetus. This increase in Eng would cause a likewise increase in sEng, via cell surface proteolytic cleavage. The excess sEng would bind to and neutralize a greater portion of the TGF-β1. Less circulating TGF-β1 molecules that are capable of binding the Eng coreceptor leads to reduced activation of the eNOS enzyme and reduced vasodilation (Venkatesha 2006). In this theory the response to the problem further exacerbates the problem most likely because there is no corresponding increase in TGF-β. This theory would indicate that sEng could be another candidate for a molecular predictor of preeclampsia early on in pregnancy.

The role of tumor necrosis factor-α in preeclampsia

The stimulus for the production of AT1-AA is another question that is troubling researchers. A 2008 study on pregnant rats showed that poor placental implantation stimulated the release of tumor necrosis factor-α (TNF-α) and that TNF-α through an unknown signaling pathway caused an increase in the circulating concentration of AT1-AA (LaMarca 2008). The impetus for the release of AT1-AA in this experiment was exogenous TNF-α. It has been propose that high levels of AT1-AA after fertilization cause poor implantation, but this study seems to indicate that poor placental implantation comes first (LaMarca 2008).

TNF-α is a pro-inflammatory cytokine involved in the immune response that has been shown to be released under hypoxic conditions in the placental by the cells of the trophoblast (Irani 2010). The release of TNF-α then causes migration of macrophages to the trophoblast cells and inhibits the placental formation (Cackovic 2008). If the implantation of the placenta is not deep enough from the beginning, the hypoxic conditions that result can then cause the release of pro-inflammatory cytokines. The circulating pro-inflammatory cytokines then exacerbate the condition. The migration of molecules from the innate and adaptive immune response to an area can create localized swelling which will further occlude the path of blood to the fetus (Irani 2010). Fetal and placenta tissue is also tissue that is foreign to the mother and it is conceivable that once the immune system is revved up by the hypoxia immune response to placenta tissue could happen. The complex pathogenesis of preeclampsia is likely one without a single causative agent but the interaction between several factors that goes awry.

The role of leptin in preeclampsia

Leptin is an adipokine that is released from adipose tissue. TNF-α is also a related adipokine (Nakatsukasa 2008). Classically leptin is a hormone thought mainly to control satiety and modulate effects related to feeding behavior. Leptin is now being studied in relationship to the pathogenesis of preeclampsia. Leptin is being labeled as a factor that modulates placental and fetal development. Rise in plasma leptin levels during pregnancy are similar to human chorionic gonadotropin. The plasma leptin levels have been shown to be higher in preeclamptic women than normotensive women, regardless of the mother's body mass index. There is however a significant inverse relationship between leptin levels and sFlt 1 levels (Nakatsukasa 2008). This relationship would suggest a mechanism different than that proposed by the AT1-AA. The way in which leptin would modulate the inhibition of s Flt 1, but could still play a role in preeclampsia is question that has not yet been answered.


The well-established theory of progesterone binding the mineralcorticoid receptor in the kidney is a very myopic view of the disease. The effect that the AT1-AA has on preeclampsia is very complex. Binding of AT1-AA to the Ang II receptors activates intracellular signaling cascades that function to raise blood pressure. AT1-AA works to increase the plasma concentration of sFlt-1, sEng, TF, PAI-1 and probably aldosterone. The complex effects that uncontrolled expression of these factors is diagrammed in Figure 2. Each one of these factors has secondary effects and target cells that also work to raise blood pressure. Since AT1-AA is not regulated by any known mechanism its uncontrolled release raises blood pressure until the placenta is delivered. This occurrence does provide one clue as to the origin of AT1-AA. If the symptoms desist


sFlt 1





Inhibits fibrinolysis

Increases Na+ reabsorption

Inhibits placental implantation

Increases fibrin coagulation

Inhibits angiogenesis and vasodilation

Figure 2.after the delivery of the placenta then, it is conceivable that the AT1-AA is being secreted from cells of the placenta. After all, the placenta is a foreign tissue in the body, why wouldn't it elicit an immune response? A possible humoral immune response to a placental antigen that is similar in structure to the AT1 receptor could exist and then without removal of the antigen the immune system begins its elaborate signaling cascade. This then causes AT1-AA to be made in large quantities until the placenta is expelled from the body. After pregnancy the immune system stops making the antibody and the symptoms cease.

The role of placental implantation also seems to be a factor that is fundamental in the pathogenesis of preeclampsia. Poor placental implantation resulting in poor fetal blood perfusion and hypoxia causes the release of TNF-α. Recent evidence also implicates leptin in preeclampsia, but the inhibition of sFlt 1 by leptin is puzzling. It is possible that two different mechanisms are at work in preeclamptic women with different molecular mechanisms but similar clinical presentations. Future avenues of research should continue to look at the source of AT1-AA. The role of leptin, TNF-α and the MR in preeclampsia should also be further explored in ongoing research.

Literature Cited:

Cackovic M, Buhimschi CS, Zhao G, et al. Fractional excretion of tumor necrosis factor-α in women with severe preeclampsia. Journal of Obstetrics & Gynecology 112: 93-100, 2008.

Celi A, Del Florentino A, Cianchetti S, et al. Tissue factor modulation by angiotensin II: a clue to a better understand of the cardiovascular effects of renin-angiotensin system blockade? Endocrine, Metabolic & Immune Disorders-Drug Targets 8: 308-313, 2008.

Chaiworapongsa T, Romero R, Kusanovic JP, et al. Plasma soluble endoglin concentration in pre-eclampsia is associated with an increased impedance to flow in the maternal and fetal circulations. Ultrasound Obstetrics & Gynecology 35:155-162, 2010.

Cudmore M, Ahmad S, Al-Ani B, et al. Negative regulation of soluble Flt-1 and soluble endoglin by heme oxygenase-1. Circulation: Journal of the American Heart Association 115: 1789-1797, 2007.

Dechend R, Homuth V, Wallukat G, et al. AT1 receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor. Circulation: Journal of the American Heart Association 101: 2382-2387, 2000.

Duckitt K and Harrington D. Risk factors for preeclampsia at antenatal booking: systematic review of controlled studies. British Medical Journal 330: 565-567, 2005.

England LJ, Levine LJ, Mills JL, et al. Adverse pregnancy outcomes in snuff users. American Journal of Obstetrics & Gynecology 189: 939-943, 2003.

Estellés A, Gilabert J, Grancha S, et al. Abnormal expression of type 1 plasminogen activator inhibitor and tissue factor in severe preeclampsia. Thrombosis and Haemostasis 79: 500-508, 1998.

Geller DS, Farhi A, Pinkerton N, et. al. Activating mineralcorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 289: 119-123, 2000.

Grill S, Rusterholz C, Zanetti-Dallenbäch R, et al. Potential makers of preeclampsia-a review. Reproductive Biology and Endocrinology 7: 70, 2009.

Hanssens M, Pijenborg R, Keirse MJNC, et al. Renin-like immunoreactivity in uterus and placenta from normotensive and hypertensive pregnancies. European Journal of Obstetrics &Gynecology and Reproductive Biology 81: 177-184, 1998.

Herse F, Verlohren S, Wenzel K et al. Prevalence of agonistic autoantibodies against the angiotensin type 1 receptor and soluble fms-like tyrosine kinase 1 in a gestational age-matched case study. Hypertension 53: 393-398, 2009.

Irani RA, Zhang Y, Zhou CC, et al. Autoantibody-mediated angiotensin receptor activation contributes to preeclampsia through tumor necrosis factor-α signaling. Hypertension 55: 1246-1253, 2010.

LaMarca B, Wallukat G, Llinas M, et al. Autoantibodies to the angiotensin type 1 receptor in response to placental ischemia and tumor necrosis factor α in pregnant rats. Hypertension 52: 1168-1172, 2008.

Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulating antiangiogenic factor in preeclampsia. The New England Journal of Medicine 355: 992-1005, 2006.

Moffett-King A. Natural killer cells and pregnancy. Nature 2: 656-663, 2002.

Mutter WP and Karumanchi SA. Molecular mechanisms of preeclampsia. Microvasc Res 75: 1-8, 2008.

Nakatsukasa H, Masuyama H, Takamoto N, et al. Circulating leptin and angiogenic factors in preeclampsia patients. Endocrine Journal 55: 565-573, 2008.

Roberts JM and Hubel CA. The two stage model of preeclampsia: Variations on the theme. PubMed Central 30: S32-S37, 2009.

Swellam M, Samy N, Wahab SA, et al. Emerging role of endothelial and inflammatory markers in preeclampsia. Disease Markers 26: 127-133, 2009.

Venkatesha S, Toporsian M, Lam C, Soluble endoglin contributes to the pathogenesis of preeclampsia. Nature Medicine 12: 642-649, 2006.

Wallukat G, Homuth V, Fischer T, et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. The Journal of Clinical Investigation 103: 945-952, 1999.

Whitlin AG and Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. American Journal of Obstetrics & Gynecology 92: 883-892, 1998.

Wikström AK, Nash P, Eriksson UJ, et al. Evidence of increased oxidative stress and a change in the plasminogen activator inhibitor (PAI-1) to PAI-2 ratio in early-onset but not late-onset preeclampsia. American Journal of Obstetrics & Gynecology 201: 597.e1-8, 2009.

Xia Y and Kellems RE. Is preeclampsia and autoimmune disease? Clinical Immunology 133: 1-12, 2009.

Zhou CC, Irani RA, Zhang Y, et al. Angiotensin receptor agonistic antibody-mediated tumor necrosis factor-α induction contributes to increased soluble endoglin production in preeclampsia. Circulation: Journal of the American Heart Association 121: 436-444, 2010.