**7. Adaptive or less adaptive**

Looking for adaptive variants is the "half-full" interpretation for the prediction of a multiple disorder like preeclampsia. The genetic scan can include adaptive genes and polymorphisms, their functional importance, i.e., effect on enzyme activity and production, their protective effect, i.e., protective from/at risk of cardiovascular disorders, pulmonary edema, thrombosis, thrombophilia, retinopathy, etc.

Earlier predictive markers for preeclampsia are believed to be in the first trimester, but it could be earlier even before the pregnancy period. Exercise stress test can be done to measure the levels of oxidative stress during and after the exercise to predict the possible response of the body. Allele and genotype frequencies of adaptive variants before the pregnancy, gene expression during and after the exercise can also be studied. In short, women who are less adaptive in their exercise have the potentials to develop preeclampsia. The same in high-altitude adaptation, women who suffer on ascent to high altitude are more likely to be preeclamptic.

"Adaptive or less adaptive" can be simply the final result of genetic tests that predict the disease, recurrence, and possible complications. DNA analysis for potential genetic markers may serve to screen for the risks of preeclampsia/eclampsia and other adverse pregnancy outcomes. Those with positive adaptive status are considered to be at decreased risk of developing preeclampsia. Certain genetic polymorphisms are attributed with certain adverse pregnancy outcomes.

### **8. Ischemic reperfusion stress: adaptation or insult**

In 1964, Martin et al. show that maternal blood flow of spiral arteries in the intervillous space is intermittent in all normal pregnancies, and they wondered if this intermittency is a mechanism for regulating maternal placental blood flow. In preeclampsia, it is believed that the process of intermittent placental perfusion (ischemic/reperfusion) secondary to deficient trophoblast invasion is a key intermediary step in the pathogenesis of preeclampsia.[37, 38].

However, the process of ischemia and reperfusion is well known to be used in clinical settings in the area of coronary heart diseases to protect the heart from the harmful effects of subsequent, prolonged ischemia by the exposure of tissues to certain degrees of intermittent periods of hypoxia and reoxygenation. The process

**47**

the 1960s.

*Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia*

sion as well as the synthesis of new proteins, including NO pathway.

suited for patients who are unable or unwilling to work out [39–41].

**8.1 Genetics and ischemic preconditioning**

can be considered as adaptive miRNAs.

termed ischemic preconditioning has been demonstrated in patients with cardiovascular disease as well as in many other organs. The process, termed ischemic preconditioning, has been demonstrated in patients with cardiovascular disease as well as in many other organs. Recent evidence suggests that there are actually two distinct types of protection afforded by preconditioning, acute and delayed preconditioning. The protective effects of acute preconditioning are protein synthesis independent in short intervals, while the effects of delayed preconditioning require protein synthesis in tissues subjected to prolonged ischemia. Delayed preconditioning appears to be an adaptation response that is dependent on altered gene expres-

It has been postulated that hypoxic preconditioning might occur normally in placentae that develop at high altitude. Laboring placentae at 3100 m have little or no oxidative stress at the time of delivery, suggesting greater resistance to ischemiareperfusion. Unlike pregnancies at sea level subjected to labor display evidence of oxidative stress. In fact, exercise can be considered as a form of remote ischemic conditioning, in which the stimulus is distant from the organ being protected. Remote ischemic conditioning has been termed "exercise in a device," especially

The question is can we consider the intermittency of maternal blood flow as a regulatory mechanism for natural hypoxic preconditioning that can occur in placentae from high altitude, and can it be the answer for the earlier question from

Ischemic preconditioning reprograms the response to ischemic injury via transcriptional changes that resemble evolutionarily conserved responses to decreased blood flow and oxygen availability. The response to ischemia alters gene expression and induces cellular adaptations and hypoxia tolerance. One of the regulatory mechanisms is the genetic reprogramming through microRNAs. MiRNA-144 and -21 have been associated with ischemic preconditioning and normal pregnancy, and

MicroRNA-144 is a circulating effector of remote ischemic preconditioning. Systemic release of microRNA-144 plays a pivotal role in inducing early and delayed cardioprotection with improved functional recovery and reduction in infarct size. Comparably, miRNA-144 was down-regulated in severe preeclampsia during the early stages of pregnancy, which supports the maladaptive nature of the disease. *MicroRNA-***21** stimulates angiogenesis by inducing VEGF production. MiRNA-21 expression is required for local and remote ischemic preconditioning in multiple organ protection, including kidneys, heart, liver, and lungs. In sport genomics, several studies support the protective role of miRNA-21 as an important regulator of exercise adaptation and in the protection of many disorders including cardiovascular disorders. In normal pregnancy, miR-21 has been shown to enhance trophoblast proliferation and invasion via modulating the nodal signaling pathway, and involve in angiogenesis process positive regulator of VEGF-A and HIF-1α. Yet, the

persistent of miRNA-21 angiogenic signal can be deleterious [42–46].

The prominent histological changes represent the structural adaptations for placental ischemia, which creates a hostile environment for the preeclamptic placentae. A number of these histopathological changes have been described; namely placental

**9. Structural adaptations of the placenta**

*DOI: http://dx.doi.org/10.5772/intechopen.86612*

#### *Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia DOI: http://dx.doi.org/10.5772/intechopen.86612*

*Prediction of Maternal and Fetal Syndrome of Preeclampsia*

EPAS-1 in normal pregnancy [3, 32–34].

**7. Adaptive or less adaptive**

retinopathy, etc.

Further experimental studies are needed to confirm the biological function of

**6.5 Methylenetetrahydrofolate reductase (MTHFR) (rs1801133, A222 V, C677T)**

The effects of MTHFR on preeclampsia are of great interest to researchers in the field. MTHFR plays a key role in homocysteine metabolism. Tibetans have an increased frequency of the homocysteine-decreasing allele of rs1801133 at the MTHFR locus more than other individuals from Eastern Asian ancestry. The homocysteine level in Tibetans is even lower than in Han, who lives at the same highlands of Tibet's but for shorter period. This renders them to be less adaptive compared to Tibetans. On the other hand, several studies found significant association at this locus with PE. The gene promoter of MTHFR is found to be hypermethylated in preeclamptic women, and this results in a high level of homocysteine. The same can

be found in high-altitude sickness as a result of mal adaptation [35, 36].

Looking for adaptive variants is the "half-full" interpretation for the prediction of a multiple disorder like preeclampsia. The genetic scan can include adaptive genes and polymorphisms, their functional importance, i.e., effect on enzyme activity and production, their protective effect, i.e., protective from/at risk of cardiovascular disorders, pulmonary edema, thrombosis, thrombophilia,

Earlier predictive markers for preeclampsia are believed to be in the first trimester, but it could be earlier even before the pregnancy period. Exercise stress test can be done to measure the levels of oxidative stress during and after the exercise to predict the possible response of the body. Allele and genotype frequencies of adaptive variants before the pregnancy, gene expression during and after the exercise can also be studied. In short, women who are less adaptive in their exercise have the potentials to develop preeclampsia. The same in high-altitude adaptation, women

"Adaptive or less adaptive" can be simply the final result of genetic tests that predict the disease, recurrence, and possible complications. DNA analysis for potential genetic markers may serve to screen for the risks of preeclampsia/eclampsia and other adverse pregnancy outcomes. Those with positive adaptive status are considered to be at decreased risk of developing preeclampsia. Certain genetic

In 1964, Martin et al. show that maternal blood flow of spiral arteries in the intervillous space is intermittent in all normal pregnancies, and they wondered if this intermittency is a mechanism for regulating maternal placental blood flow. In preeclampsia, it is believed that the process of intermittent placental perfusion (ischemic/reperfusion) secondary to deficient trophoblast invasion is a key inter-

However, the process of ischemia and reperfusion is well known to be used in clinical settings in the area of coronary heart diseases to protect the heart from the harmful effects of subsequent, prolonged ischemia by the exposure of tissues to certain degrees of intermittent periods of hypoxia and reoxygenation. The process

who suffer on ascent to high altitude are more likely to be preeclamptic.

polymorphisms are attributed with certain adverse pregnancy outcomes.

**8. Ischemic reperfusion stress: adaptation or insult**

mediary step in the pathogenesis of preeclampsia.[37, 38].

**46**

termed ischemic preconditioning has been demonstrated in patients with cardiovascular disease as well as in many other organs. The process, termed ischemic preconditioning, has been demonstrated in patients with cardiovascular disease as well as in many other organs. Recent evidence suggests that there are actually two distinct types of protection afforded by preconditioning, acute and delayed preconditioning. The protective effects of acute preconditioning are protein synthesis independent in short intervals, while the effects of delayed preconditioning require protein synthesis in tissues subjected to prolonged ischemia. Delayed preconditioning appears to be an adaptation response that is dependent on altered gene expression as well as the synthesis of new proteins, including NO pathway.

It has been postulated that hypoxic preconditioning might occur normally in placentae that develop at high altitude. Laboring placentae at 3100 m have little or no oxidative stress at the time of delivery, suggesting greater resistance to ischemiareperfusion. Unlike pregnancies at sea level subjected to labor display evidence of oxidative stress. In fact, exercise can be considered as a form of remote ischemic conditioning, in which the stimulus is distant from the organ being protected. Remote ischemic conditioning has been termed "exercise in a device," especially suited for patients who are unable or unwilling to work out [39–41].

The question is can we consider the intermittency of maternal blood flow as a regulatory mechanism for natural hypoxic preconditioning that can occur in placentae from high altitude, and can it be the answer for the earlier question from the 1960s.

#### **8.1 Genetics and ischemic preconditioning**

Ischemic preconditioning reprograms the response to ischemic injury via transcriptional changes that resemble evolutionarily conserved responses to decreased blood flow and oxygen availability. The response to ischemia alters gene expression and induces cellular adaptations and hypoxia tolerance. One of the regulatory mechanisms is the genetic reprogramming through microRNAs. MiRNA-144 and -21 have been associated with ischemic preconditioning and normal pregnancy, and can be considered as adaptive miRNAs.

MicroRNA-144 is a circulating effector of remote ischemic preconditioning. Systemic release of microRNA-144 plays a pivotal role in inducing early and delayed cardioprotection with improved functional recovery and reduction in infarct size. Comparably, miRNA-144 was down-regulated in severe preeclampsia during the early stages of pregnancy, which supports the maladaptive nature of the disease.

*MicroRNA-***21** stimulates angiogenesis by inducing VEGF production. MiRNA-21 expression is required for local and remote ischemic preconditioning in multiple organ protection, including kidneys, heart, liver, and lungs. In sport genomics, several studies support the protective role of miRNA-21 as an important regulator of exercise adaptation and in the protection of many disorders including cardiovascular disorders. In normal pregnancy, miR-21 has been shown to enhance trophoblast proliferation and invasion via modulating the nodal signaling pathway, and involve in angiogenesis process positive regulator of VEGF-A and HIF-1α. Yet, the persistent of miRNA-21 angiogenic signal can be deleterious [42–46].

### **9. Structural adaptations of the placenta**

The prominent histological changes represent the structural adaptations for placental ischemia, which creates a hostile environment for the preeclamptic placentae. A number of these histopathological changes have been described; namely placental

infarcts, increased syncytial knots, hypovascularity of the villi, increased cytotrophoblastic proliferation, thickening of the sub-trophoblastic basement membrane, obliterated enlarged endothelial cells in the fetal capillaries, and atherosis of the spiral arteries in the placental bed. The volume of the intervillous space and the terminal villi are also decreased in proportion to the degree of preeclampsia. Some of the histological features like syncytial knots, cytotrophoblastic proliferation, thickening of sub-trophoblastic basement membrane, and hypovascular villi were observed in the placentae of normotensive women in varying degrees yet within normal limits [47].

**Placental infarcts** are small yellowish-white deposits of fibrin (a fibrous protein) of the placenta caused by the inadequate blood supply. They occur normally in the placenta as pregnancy progresses, and account about 25–30% of term normal pregnancies. The fetus usually is not affected by infarction of the placenta, unless the process is extensive. However, infarcts are found in nearly all cases of moderate or severe PIH. They are strongly associated with pregnancy-induced hypertension (PIH) and with growth-restricted babies. Moreover, several studies have found a direct correlation between the degree of PIH and the amount of infarction of the placenta. At molecular levels, plasminogen activator inhibitors (PAI-1/PAI-2), which regulate fibrinolysis, could be responsible for the very high levels of fibrin deposition in the intervillous space and the placental infarction observed in these pregnancies. The hypofibrinolytic genotypes 4G/4G and A/A of the PAI-1 gene are associated with the occurrence of mild preeclampsia. The insertion/deletion PAI-1 4G/5G polymorphism (rs1799889) was also found to have a significant association with preeclampsia [48, 49].

**Acute atherosis** is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis, and perivascular lymphocytic infiltration. This lesion is generally confined to non-transformed spiral arteries and is frequently observed in patients with preeclampsia. In early-onset preeclamptic patients, the polymorphisms in the regulator of G protein signaling 2 gene (RGS2) 3′UTR (C1114G, rs4606) of CG or GG genotype is more frequent in decidual spiral arteries in women with acute atherosis (resembling early stage of atherosclerosis). PIA-1, as an important regulator within the fibrinolytic system, has also been shown to be a risk indicator for venous and arterial thrombosis [50, 51].

**Retroplacental hematoma (placental abruption)** is having bleeding behind the placenta. This happens when the placenta starts separating prematurely due to bleeding and instability of uteroplacental vessels. The maternal MTHFR C677T polymorphism was found to be a risk factor for placental abruption. This agrees with the association of hyperhomocysteinemia with placental abruption [52, 53].

**Syncytial knots:** For oxygen requirement, the syncytium depends on the maternal blood flow to the intervillous space through the uteroplacental circulation. Reduced uteroplacental blood flow in hypertension may result in hypoxic damage to the syncytium. The damaged syncytium stimulates syncytial nuclear proliferation leading to syncytial knots formation. In an attempt to replace the degenerated syncytium, the cytotrophoblast cells undergo proliferation. Increased numbers of syncytial knots have been reported in placentae of pregnancies complicated by preeclampsia, probably to be induced by hypoxia. Syncytins 1 and 2 genes play a crucial role in trophoblast fusion stage of syncytial knot formation [47, 54].

#### **10. The cross talk between syncytiotrophoblast and other remote organs**

**49**

anterior pituitary [58].

*Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia*

complications involving placental dysfunction [55, 56].

maternal circulation. There are extracellular vesicles often referred to as syncytiotrophoblast extracellular vesicles (STBEVs) due to their syncytiotrophoblast cell of origin. They are believed to play an important role both in normal and dysfunctional pregnancies. They are released in form of exosomes, microvesicles, and apoptotic bodies that carry many syncytiotrophoblast derived factors such as mRNA, miRNA, proteins, and lipids. This gives a potentially rich source of biomarkers in

**Vascular endothelial cells:** In preeclampsia, there is an increased release of placental STBEVs into the maternal circulation. It has been suggested that release of factors from the placenta in response to ischemia results in endothelial dysfunction of the maternal circulation. As a result, an imbalance of anticoagulation and procoagulation forces is found in preeclampsia as increases in proteins of the coagulation cascade, proangiogenic and antiangiogenic imbalance resulting in high sflt-1 levels that inactivate VEGF function, increased adhesion cell molecules are also significantly elevated including VCAM-1, ICAM-1, and E-selectin. An example of angiogenic imbalance is the syncytial knots that are enriched with sFlt1 protein. At least 25% of the measurable sFlt1 in the third-trimester maternal plasma is bound to circulating placental microparticles. The free detached syncytial knots are loaded with sFlt1 protein and mRNA. These findings suggest that STBEVs may cause endothelial damage and contribute to the endothelial dysfunction [57].

**Paranchymal organs:** In general, the histological changes, mainly in eclamptic phase of preeclampsia, are hemorrhagic and thrombotic in nature. They are found in the main parenchymatous organs: liver, kidneys, placenta, brain, and adrenals. The liver lesions, when present, take the form of irregular, focal subcapsular, and intraparenchymal hemorrhages. On histologic examination, there are fibrin thrombi in the portal capillaries and foci of hemorrhagic necrosis. The kidney lesions are variable. The glomeruli show marked swelling of endothelial cells, amorphous dense deposits on the endothelial side of the basement membrane, and mesangial cell hyperplasia. Immunofluorescent studies show an abundance of fibrin in glomeruli. In advanced cases, fibrin thrombi are present in the glomeruli and capillaries of the cortex. If widespread and severe, these thrombi may produce complete destruction of the cortex in the pattern referred to as bilateral renal cortical necrosis. The brain may have gross or microscopic foci of hemorrhage along with small vessel thrombosis. Similar changes are often found in the heart and the

At molecular level, circulating STBEVs can directly affect these remote organs

(**Figure 2**). An example of this is the STBEVs uptake by the primary human coronary artery endothelial cells and the transfer of placenta specific miRNAs from STBEVs inside these recipient cells. The transferred miRNAs were functional, causing a downregulation of specific target genes, including the PE associated gene fms related tyrosine kinase 1 (FLT1). This suggests the ability of the placenta for endothelial reprogramming that may underlay the increased risk of cardiovascular disease reported for women with preeclampsia later in life. In kidneys, renal ischemic preconditioning up-regulates the expression of microRNA-21 in serum extracellular vesicles of exosomes in kidney and remote organs. This results in decreased apoptosis and reduced proinflammatory cytokines production in multiple organs including kidneys, heart, liver, and lungs. Another example is the role of STBEVs in thrombi formation. STBEVs released from preeclamptic placenta exhibit increased procoagulant tissue factor activity. Tissue factor is the primary initiator of coagulation in vivo. The increased numbers of circulating STBEVs in the blood of women with preeclampsia, along with the greater expression of tissue factor on preeclampstic STBEVs would be expected to comprise a substantial intravascular pro-thrombotic stimulus. A majority of deep venous thrombosis

*DOI: http://dx.doi.org/10.5772/intechopen.86612*

Throughout pregnancy, the cross talk between the placenta and other parts of the body is mainly relying on messages released from the syncytium into the

#### *Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia DOI: http://dx.doi.org/10.5772/intechopen.86612*

*Prediction of Maternal and Fetal Syndrome of Preeclampsia*

normal limits [47].

with preeclampsia [48, 49].

and arterial thrombosis [50, 51].

infarcts, increased syncytial knots, hypovascularity of the villi, increased cytotrophoblastic proliferation, thickening of the sub-trophoblastic basement membrane, obliterated enlarged endothelial cells in the fetal capillaries, and atherosis of the spiral arteries in the placental bed. The volume of the intervillous space and the terminal villi are also decreased in proportion to the degree of preeclampsia. Some of the histological features like syncytial knots, cytotrophoblastic proliferation, thickening of sub-trophoblastic basement membrane, and hypovascular villi were observed in the placentae of normotensive women in varying degrees yet within

**Placental infarcts** are small yellowish-white deposits of fibrin (a fibrous protein) of the placenta caused by the inadequate blood supply. They occur normally in the placenta as pregnancy progresses, and account about 25–30% of term normal pregnancies. The fetus usually is not affected by infarction of the placenta, unless the process is extensive. However, infarcts are found in nearly all cases of moderate or severe PIH. They are strongly associated with pregnancy-induced hypertension (PIH) and with growth-restricted babies. Moreover, several studies have found a direct correlation between the degree of PIH and the amount of infarction of the placenta. At molecular levels, plasminogen activator inhibitors (PAI-1/PAI-2), which regulate fibrinolysis, could be responsible for the very high levels of fibrin deposition in the intervillous space and the placental infarction observed in these pregnancies. The hypofibrinolytic genotypes 4G/4G and A/A of the PAI-1 gene are associated with the occurrence of mild preeclampsia. The insertion/deletion PAI-1 4G/5G polymorphism (rs1799889) was also found to have a significant association

**Acute atherosis** is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis, and perivascular lymphocytic infiltration. This lesion is generally confined to non-transformed spiral arteries and is frequently observed in patients with preeclampsia. In early-onset preeclamptic patients, the polymorphisms in the regulator of G protein signaling 2 gene (RGS2) 3′UTR (C1114G, rs4606) of CG or GG genotype is more frequent in decidual spiral arteries in women with acute atherosis (resembling early stage of atherosclerosis). PIA-1, as an important regulator within the fibrinolytic system, has also been shown to be a risk indicator for venous

**Retroplacental hematoma (placental abruption)** is having bleeding behind the placenta. This happens when the placenta starts separating prematurely due to bleeding and instability of uteroplacental vessels. The maternal MTHFR C677T polymorphism was found to be a risk factor for placental abruption. This agrees with the association of hyperhomocysteinemia with placental abruption [52, 53]. **Syncytial knots:** For oxygen requirement, the syncytium depends on the maternal blood flow to the intervillous space through the uteroplacental circulation. Reduced uteroplacental blood flow in hypertension may result in hypoxic damage to the syncytium. The damaged syncytium stimulates syncytial nuclear proliferation leading to syncytial knots formation. In an attempt to replace the degenerated syncytium, the cytotrophoblast cells undergo proliferation. Increased numbers of syncytial knots have been reported in placentae of pregnancies complicated by preeclampsia, probably to be induced by hypoxia. Syncytins 1 and 2 genes play a crucial role in trophoblast fusion stage of syncytial knot formation [47, 54].

**10. The cross talk between syncytiotrophoblast and other remote organs**

Throughout pregnancy, the cross talk between the placenta and other parts of the body is mainly relying on messages released from the syncytium into the

**48**

maternal circulation. There are extracellular vesicles often referred to as syncytiotrophoblast extracellular vesicles (STBEVs) due to their syncytiotrophoblast cell of origin. They are believed to play an important role both in normal and dysfunctional pregnancies. They are released in form of exosomes, microvesicles, and apoptotic bodies that carry many syncytiotrophoblast derived factors such as mRNA, miRNA, proteins, and lipids. This gives a potentially rich source of biomarkers in complications involving placental dysfunction [55, 56].

**Vascular endothelial cells:** In preeclampsia, there is an increased release of placental STBEVs into the maternal circulation. It has been suggested that release of factors from the placenta in response to ischemia results in endothelial dysfunction of the maternal circulation. As a result, an imbalance of anticoagulation and procoagulation forces is found in preeclampsia as increases in proteins of the coagulation cascade, proangiogenic and antiangiogenic imbalance resulting in high sflt-1 levels that inactivate VEGF function, increased adhesion cell molecules are also significantly elevated including VCAM-1, ICAM-1, and E-selectin. An example of angiogenic imbalance is the syncytial knots that are enriched with sFlt1 protein. At least 25% of the measurable sFlt1 in the third-trimester maternal plasma is bound to circulating placental microparticles. The free detached syncytial knots are loaded with sFlt1 protein and mRNA. These findings suggest that STBEVs may cause endothelial damage and contribute to the endothelial dysfunction [57].

**Paranchymal organs:** In general, the histological changes, mainly in eclamptic phase of preeclampsia, are hemorrhagic and thrombotic in nature. They are found in the main parenchymatous organs: liver, kidneys, placenta, brain, and adrenals. The liver lesions, when present, take the form of irregular, focal subcapsular, and intraparenchymal hemorrhages. On histologic examination, there are fibrin thrombi in the portal capillaries and foci of hemorrhagic necrosis. The kidney lesions are variable. The glomeruli show marked swelling of endothelial cells, amorphous dense deposits on the endothelial side of the basement membrane, and mesangial cell hyperplasia. Immunofluorescent studies show an abundance of fibrin in glomeruli. In advanced cases, fibrin thrombi are present in the glomeruli and capillaries of the cortex. If widespread and severe, these thrombi may produce complete destruction of the cortex in the pattern referred to as bilateral renal cortical necrosis. The brain may have gross or microscopic foci of hemorrhage along with small vessel thrombosis. Similar changes are often found in the heart and the anterior pituitary [58].

At molecular level, circulating STBEVs can directly affect these remote organs (**Figure 2**). An example of this is the STBEVs uptake by the primary human coronary artery endothelial cells and the transfer of placenta specific miRNAs from STBEVs inside these recipient cells. The transferred miRNAs were functional, causing a downregulation of specific target genes, including the PE associated gene fms related tyrosine kinase 1 (FLT1). This suggests the ability of the placenta for endothelial reprogramming that may underlay the increased risk of cardiovascular disease reported for women with preeclampsia later in life. In kidneys, renal ischemic preconditioning up-regulates the expression of microRNA-21 in serum extracellular vesicles of exosomes in kidney and remote organs. This results in decreased apoptosis and reduced proinflammatory cytokines production in multiple organs including kidneys, heart, liver, and lungs. Another example is the role of STBEVs in thrombi formation. STBEVs released from preeclamptic placenta exhibit increased procoagulant tissue factor activity. Tissue factor is the primary initiator of coagulation in vivo. The increased numbers of circulating STBEVs in the blood of women with preeclampsia, along with the greater expression of tissue factor on preeclampstic STBEVs would be expected to comprise a substantial intravascular pro-thrombotic stimulus. A majority of deep venous thrombosis

#### **Figure 2.**

*The role of syncytiotrophoblast extracellular vesicles (STBEVs) in the cross talk between the placenta and other tissues and organs include exosomes, microvesicles, apoptotic bodies, and syncytial knots. Adequate blood flow from a limited number of EVs are shed from the placenta into the maternal circulation, while increased number of STBEVs are shed from preeclamptic placenta. The cargo of STBEVs including microRNAs, mRNAs, proteins, lipids, and glycans may be "planned" by the placenta. This cargo controls gene expression in vascular endothelial cells and other tissues and organs. STBEVs contents and deportations are controlled by the placental hypoxia. In preeclampsia, high levels of hypoxia lead to reduce syncytin-1 expression, and thus increased syncytial knots deportation [64].*

occur within the valve pockets of deep venous valves that are exposed to "periods of stasis" and low oxygen levels, resembling the I/R oxidative stress. Venous valves have adapted to this phenomenon by expressing higher levels of anticoagulants thrombomodulin and endothelial cell protein C receptor, which are both decreased in preeclampsia [59–61].

To conclude, the high degree of concordance between placental lesions and gene expression across different subtypes of preeclampsia, reflects the importance of appropriate communication in successful pregnancy [62, 63].

#### **11. Evolutionary steps: from preeclamptic cells, cancer to adaptive cells**

Preeclamptic cells are genetically late compared to cancer cells, and this is probably the reason behind their protection from cancer. For example, angiogenesis are balanced in normal cells, and shift to the lift in preeclampsia and to the right in cancer cells and adaptive cells. The shift of preeclamptic cells from the left to the right can take longer time (**Figure 3**). Longer prospective studies show that preeclamptic women can lose their protective advantage by time, while adaptive individuals, according to the evolutionary steps, can show better protection than preeclamptic cells [65]. Normal cells can avoid cancer and jump to adaptive status by gradual adaptation or preconditioning. This is why normal multiple pregnancies are naturally protected from cancer and other oxidative stress disorders, due to their intermittent exposure to hypoxia that act as natural ischemic preconditioning. Accordingly, both preeclamptic cells and adaptive cells are protective against cancer, but for different reasons. In a different context, cancer cells, due to their high cellular turnout and high evolutionary rate, have a higher ability to gain mutations,

**51**

**Conflict of interest**

The author declares no conflict of interest.

*Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia*

and thus have a high probability for adaptive mutations. This can be used to study the protective function of adaptive variants in pregnancy and preeclampsia under

*Evolutionary steps from preeclamptic cells, normal cells, cancer cells, and adaptive cells.*

Future genetic studies are required for assaying additional adaptive variants near the candidate, HIF-targeted and -regulatory genes for testing functionality, and verify the existence of natural selection [9]. Such studies present a novel and relatively unexplored approach that enable the normal cells to adapt to their scarce microenvironment to the highest possible extent. No matter of the reasons that lead to preeclampsia, which are probably different, the advanced integrated biological system of genetic and epigenetic adaptive polymorphisms can "vaccinate" the body against the detrimental consequences and complications of the disease, and can reflect the ability of the body for survival and recovery. Methods of inducing natural adaptive mechanisms, like in ischemic preconditioning, has been attempted in clinical practice in the area of coronary heart disease in an attempt to limit the injury caused to the heart via ischemia and reperfusion injury. Such injury would occur when a patient has an acute myocardial infarction followed by reperfusion by either percutaneous coronary intervention or thrombolysis. Although, placental preconditioning was suggested to occur as an adaptive response to the hypobaric hypoxia at high altitudes, the area of placental preconditioning in clinical practice is yet to be explored. At molecular levels, adaptation to hypoxia can enhance the ability of the placenta to acquire genetic adaptive experience resulting in a stress relief, protection, and probably recovery in subsequent pregnancies. The messages released from the placenta into the maternal circulation transfer the genetic experience throughout the body. It can dramatically modify the histological picture in the placenta and other remote organs, and modulate the function of these organs.

*DOI: http://dx.doi.org/10.5772/intechopen.86612*

different stressful conditions.

**12. Conclusion**

**Figure 3.**

*Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia DOI: http://dx.doi.org/10.5772/intechopen.86612*

**Figure 3.** *Evolutionary steps from preeclamptic cells, normal cells, cancer cells, and adaptive cells.*

and thus have a high probability for adaptive mutations. This can be used to study the protective function of adaptive variants in pregnancy and preeclampsia under different stressful conditions.
