**12. Conclusion**

*Prediction of Maternal and Fetal Syndrome of Preeclampsia*

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

*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* 

To conclude, the high degree of concordance between placental lesions and gene expression across different subtypes of preeclampsia, reflects the importance of

**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,

appropriate communication in successful pregnancy [62, 63].

**50**

in preeclampsia [59–61].

*syncytial knots deportation [64].*

**Figure 2.**

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.
