**1. Introduction**

Throughout the lives of individuals, their genes interact with their environments to cause variations in phenotype traits. Because individuals with certain traits tend to survive and reproduce more than others with less successful traits, the population evolves. In 1859, Charles Darwin set out his theory of evolution by natural selection as an explanation for adaptation and speciation. He defined natural selection as the "principle by which each slight variation [of a trait], if useful, is preserved" [1]. Although the Darwinian theory was ages before the genome era, it can also explain the process of natural selection at molecular levels; cells with successful traits are best adapted to their microenvironments, and more likely to survive and proliferate. The selection between cells favors those with the most advantageous genetic polymorphisms. The genetic variability is usually enhanced by the scarce microenvironments like low oxygen, low temperature, and high radiation that act as competitive milieus for cells. The useful genetic variants are preserved and can be heritable.

Some 2.4 billion years ago, photosynthesis leads to the accumulation of oxygen to levels that were likely toxic to many microorganisms. Organisms that could

defend themselves against oxidative stress and at the same time utilize oxygen for energy, survived and evolved. As time went on, cellular requirement for oxygen became critical, and animals developed a physiological response to the low levels of oxygen. The cellular ability to compete in such scarce microenvironments became the "microevolutionary" exam for survival in many physiological processes as in hematopoiesis, spermatogenesis, normal pregnancy, and embryogenesis. Genetic studies suggest that hypoxia-inducible factors (HIFs) are a family of master transcriptional regulators for the hypoxic response inside the body. HIF-α transcription factors (HIF-1α and HIF-2α/EPAS1) dimerize with HIF-1β/ARNT subunits, and translocate to the nucleus, where it binds to the hypoxia responsive element (HRE) in the genetic material to regulate the transcription of some 200 genes, leading to the adaptive response to hypoxic stress. In turn, hypoxia responsive genes promote the tolerance of hypoxia by decreasing the cellular requirement for oxygen and increasing the supply of oxygen. They mainly involved in angiogenesis, erythropoiesis, energy metabolism, and autophagy [2].

On ascent to high attitudes, lowlanders become at risk of conditions like acute mountain sickness (AMS), pulmonary edema, cerebral edema, and polycythemia in the chronic type of the disease. These conditions, which resemble many symptoms associated with preeclampsia, are considered to be a maladaptive response to the low oxygen levels at high altitudes. However, ancient indigenous populations like Tibetans through generations acquired unique integrated physiological processes for defending their body against oxygen deprivation. This gives them the advantage of being protected from hypoxia-related disorders, like hypertension, diabetes mellitus, cardiovascular disorders, and preeclampsia. Yet, physiological acclimatization can occur in lowlanders over days to weeks following ascent and can serve as the first steps of adaptation. This led to the idea that adaptation to hypoxia can also protect from pathological disorders that result in dysregulation of hypoxia pathways like in preeclampsia [3].

#### **2. Preeclampsia as a maladaptive disorder**

In spite of the extensive research in the pathophysiology of the disease, the etiology is still poorly understood. It was suggested to be due to the insufficient adaptation of spiral arterioles or due to the shallow trophoblastic invasion, resulting in reduced uteroplacental blood flow leading to placental hypoxia. The placenta initially develops in a low oxygen environment of 1–2% oxygen until after the 10th week of pregnancy. This maternal hypoxia is an effective stimulus eliciting adaptations at the maternal-fetal interface, which include activation of the invasive endovascular trophoblast cell lineage and modifications of uterine blood vessels supplying the developing chorioallantoic placenta. Reduced or absent cytotrophoblast invasion of the maternal uterine spiral arterioles is a common clinical finding in studies of pregnancies complicated by preeclampsia, suggesting that the mechanism mediating invasion of these cells is perturbed. While, it is proposed that hypoxia-inducible factors are the key regulators of the first trimester [4–7].

The exposure of pregnant women to hypobaric hypoxia at high altitudes leads to arterial maternal hypoxia and intervillous blood hypoxia at the maternal-fetal interface. This renders pregnant women from low-altitude to be at risk of many complications including reproductive loss, intrauterine growth restriction, and preeclampsia. However, high-altitude residents have low rates of preeclampsia compared to other populations at the same altitudes. Such population differences are due, at least in part, to differences in maternal vascular responses to pregnancy. It was hypothesized that natural selection acting on hypoxia-inducible factor

**41**

outcome.

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

(HIF)-targeted or -regulatory genes has enabled maternal vascular adaptation to pregnancy in long-resident high-altitude groups. Earlier studies support this hypothesis and demonstrate that the potent genes can be differentially regulated between adaptive and less adaptive populations. Moore et al. show that HIFtargeted vasoconstrictor, endothelin-1 (ET-1), is differentially regulated by pregnancy in Andean vs. European residents at high altitudes. Andeans, who live longer at high altitude, show normal, pregnancy-associated fall in ET-1 levels; whereas, Europeans have higher ET-1 levels and little pregnancy-associated change, like in preeclamptic women. Another hopeful study revealed that high-altitude Tibetans, who have lived the longest at high altitude, can share similar genotypic and allelic frequencies of adaptive variants with sea level Sojourners who undergo acclimatiza-

This led to the question that, if lowlanders on ascent have the ability to acquire allele and genotype frequency as in adaptive native individuals, can preeclamptic women undergo acclimatization, and can it be used as a predictive marker for the

**3. From preeclampsia to normal pregnancy: the hidden adaptation!**

There are a very large number of both prospective and retrospective studies investigating the preeclampsia recurrence rate, with different sample sizes, target populations, study designs, and main outcome measures, resulting in contrasting conclusions. Yet, maternal and perinatal outcomes in the subsequent pregnancy are generally better than in the first; most women will not have recurrent preeclampsia, and those who do usually will give birth at a greater gestational age compared with their index birth. Even though, women who have experienced a pregnancy complicated by preeclampsia, including their caregivers, undoubtedly have a fear of recurrence and should be counseled about their reproductive future. Many of these mothers and babies are at increased risk of severe adverse outcomes that include acute renal or hepatic failure, antepartum and postpartum hemorrhage, stroke, maternal death, intrauterine growth restriction, and perinatal death. Long-term, the burden of preterm birth is immense, particularly in terms of neurodevelopmental impairment, impaired learning, cerebral palsy, and need for special care

Another evidence for the hidden adaptation is the ability of the placenta to survive the oxidative stress. Uterine artery Doppler studies are proposed to be abnormal in the second trimester of pregnancy because of increased vascular resistance indicating failed remodeling of the vessels of the intervillous space. About half of women with abnormal uterine artery Doppler findings go on to have preeclampsia, preterm birth, or pregnancies complicated by IUGR, while, the other half go on to normal outcomes. Besides to the Doppler scans, biochemical markers, like reduced circulating ascorbate, increased concentrations of nitric oxide synthase, and AT1 angiotensin receptor inhibitors, show evidence of oxidative stress both in women with or without abnormal uterine artery velocimetry. These markers are present regardless of whether the pregnancy proceeds to IUGR, preeclampsia, or a normal

These findings support the concept that poor placentation (Stage 1 of the model) alone is not sufficient to cause preeclampsia, and that there are other factors that adjust the physiological wheel of oxidative stress toward adaptation and normal pregnancy or toward preeclampsia (stage 2 of the model) [12]. In other words, it appears that the placenta starts as preeclamptic, and then somehow overcomes the oxidative stress and continues the placentation normally. This raises many questions

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

tion on ascent [8–10].

disease.

resources [11].

*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*

esis, energy metabolism, and autophagy [2].

**2. Preeclampsia as a maladaptive disorder**

like in preeclampsia [3].

defend themselves against oxidative stress and at the same time utilize oxygen for energy, survived and evolved. As time went on, cellular requirement for oxygen became critical, and animals developed a physiological response to the low levels of oxygen. The cellular ability to compete in such scarce microenvironments became the "microevolutionary" exam for survival in many physiological processes as in hematopoiesis, spermatogenesis, normal pregnancy, and embryogenesis. Genetic studies suggest that hypoxia-inducible factors (HIFs) are a family of master transcriptional regulators for the hypoxic response inside the body. HIF-α transcription factors (HIF-1α and HIF-2α/EPAS1) dimerize with HIF-1β/ARNT subunits, and translocate to the nucleus, where it binds to the hypoxia responsive element (HRE) in the genetic material to regulate the transcription of some 200 genes, leading to the adaptive response to hypoxic stress. In turn, hypoxia responsive genes promote the tolerance of hypoxia by decreasing the cellular requirement for oxygen and increasing the supply of oxygen. They mainly involved in angiogenesis, erythropoi-

On ascent to high attitudes, lowlanders become at risk of conditions like acute mountain sickness (AMS), pulmonary edema, cerebral edema, and polycythemia in the chronic type of the disease. These conditions, which resemble many symptoms associated with preeclampsia, are considered to be a maladaptive response to the low oxygen levels at high altitudes. However, ancient indigenous populations like Tibetans through generations acquired unique integrated physiological processes for defending their body against oxygen deprivation. This gives them the advantage of being protected from hypoxia-related disorders, like hypertension, diabetes mellitus, cardiovascular disorders, and preeclampsia. Yet, physiological acclimatization can occur in lowlanders over days to weeks following ascent and can serve as the first steps of adaptation. This led to the idea that adaptation to hypoxia can also protect from pathological disorders that result in dysregulation of hypoxia pathways

In spite of the extensive research in the pathophysiology of the disease, the etiology is still poorly understood. It was suggested to be due to the insufficient adaptation of spiral arterioles or due to the shallow trophoblastic invasion, resulting in reduced uteroplacental blood flow leading to placental hypoxia. The placenta initially develops in a low oxygen environment of 1–2% oxygen until after the 10th week of pregnancy. This maternal hypoxia is an effective stimulus eliciting adaptations at the maternal-fetal interface, which include activation of the invasive endovascular trophoblast cell lineage and modifications of uterine blood vessels supplying the developing chorioallantoic placenta. Reduced or absent cytotrophoblast invasion of the maternal uterine spiral arterioles is a common clinical finding in studies of pregnancies complicated by preeclampsia, suggesting that the mechanism mediating invasion of these cells is perturbed. While, it is proposed that

hypoxia-inducible factors are the key regulators of the first trimester [4–7].

The exposure of pregnant women to hypobaric hypoxia at high altitudes leads to arterial maternal hypoxia and intervillous blood hypoxia at the maternal-fetal interface. This renders pregnant women from low-altitude to be at risk of many complications including reproductive loss, intrauterine growth restriction, and preeclampsia. However, high-altitude residents have low rates of preeclampsia compared to other populations at the same altitudes. Such population differences are due, at least in part, to differences in maternal vascular responses to pregnancy. It was hypothesized that natural selection acting on hypoxia-inducible factor

**40**

(HIF)-targeted or -regulatory genes has enabled maternal vascular adaptation to pregnancy in long-resident high-altitude groups. Earlier studies support this hypothesis and demonstrate that the potent genes can be differentially regulated between adaptive and less adaptive populations. Moore et al. show that HIFtargeted vasoconstrictor, endothelin-1 (ET-1), is differentially regulated by pregnancy in Andean vs. European residents at high altitudes. Andeans, who live longer at high altitude, show normal, pregnancy-associated fall in ET-1 levels; whereas, Europeans have higher ET-1 levels and little pregnancy-associated change, like in preeclamptic women. Another hopeful study revealed that high-altitude Tibetans, who have lived the longest at high altitude, can share similar genotypic and allelic frequencies of adaptive variants with sea level Sojourners who undergo acclimatization on ascent [8–10].

This led to the question that, if lowlanders on ascent have the ability to acquire allele and genotype frequency as in adaptive native individuals, can preeclamptic women undergo acclimatization, and can it be used as a predictive marker for the disease.
