**4. Conclusions**

The most common conditions encountered during pathological pregnancy are hypertensive complications, including PE, PIH, and maternal chronic hypertension. PE is a systemic syndrome affecting about 5–8% of all pregnancies. It is characterized by new onset of hypertension and proteinuria after 20 weeks of gestation and is a major cause of maternal mortality (15–20% in developed countries) and one of the major causes of infant morbidity and mortality, perinatal deaths, preterm birth, and intrauterine growth restriction [246–248].

PE may be the result of abnormal activation of the maternal immune system characterized by endothelial dysfunction and excessive inflammation [57,112,113,206,239,241]. Knowledge regarding the involvement of the immune system in both hypertension and in pregnancies complicated by PE has evolved significantly. During pregnancy, it was believed that alterations in the levels of angiogenic/anti-angiogenic factors such as PlGF and sFlt-1/sVEGFR-1 were essentially responsible for impaired vascular placental development, increased vascular resistance of spiral arteries, and endothelial dysfunction. Today, we know that these factors also have a decisive role in modulating the maternal immune response throughout the pregnancy. They are not only accountable for alterations of immune cell behavior but also for the altered release of proinflammatory mediators and systemic involvement of the inflammatory response.

PlGF showed an important effect on the development of hypertension by modulating egress of T cells from the spleen and their accumulation in vessel walls and kidneys, even in non-pregnant mouse model [245]. It is not surprisingly that its influence is modulated by the involvement of typical pathways implicated in tumor growth. Indeed, some of the effects attributed to PlGF inhibition in cancer might rely on epigenetic modulation of the p53-Timp3 axis, which is well known to also play a crucial role in tumor growth [249], again confirming the presence of overlapping mechanisms between pregnancy and malignancy.

Presently, the diagnostic criteria of PE remain uncertain because no known specific biomarkers are available, thus, women at risk are identified based on epidemiological and clinical risk factors [250]. Many studies on PE diagnosis, which have analyzed the sFlt-1/sVEGFR-1/PlGF ratio as a predictor for poor pregnancy, have demonstrated its reliability [100,102–104]. However, PlGF imbalance during pregnancy can be due to several mechanisms, which preclude the precise identification of a specific marker useful for diagnosis. In this regard, different scenarios can be expected. On the one hand, PlGF upregulation can be accountable for the activation of an inflammatory state associated with the release of mediators such as TNF-α, IL-6, IL-17, and COX-2. These cytokines, by modulating the cells of the immune system (e.g., M1 polarized Mϕ, mature DCs, Th1 lymphocytes, reduction of Treg cells) could prevent maternal tolerance, fuel inflammation, and, at the same time, interfere with adequate vascular development of the placenta. Both of these events contribute to mechanisms that promote hypertension. On the other hand, reduced levels of PlGF, due either to inadequate production by trophoblast cells, uterine cells and uNK cells, or to its excessive sequestration by sFlt1/sVEGFR-1, can be responsible for the inadequate trophoblast invasion, the deficient vascular development and, at the same time, for a loss of maternal tolerance. Yet again, these events contribute to mechanisms that promote hypertension. Therefore, to date, a single reliable diagnostic marker is still difficult to identify. In the future, the definitive understanding of the immunological mechanisms involved in the onset of different PE phenotypes, such as placental PE associated with growth restriction, PE associated with a chronic maternal inflammatory condition, and maternal dysmetabolism associated with normal fetal growth, in which PlGF could be involved, may offer new specific diagnostic markers and therapeutic tools for managing pathological pregnancies.

**Author Contributions:** Conceptualization, L.A. and R.B.; Funding acquisition, R.B.; Supervision, L.A. and R.B.; writing—original draft, L.A. and R.B.; writing—review and editing, M.B., L.A., C.F., L.C., M.T.M., F.L., and V.M. All authors gave a significant intellectual contribution to the article. All authors have read and agreed to the published version of the manuscript.

**Funding:** The present article was supported by a grant from the University of Rome "Tor Vergata" BeiREPRVanillina (CUP: E88D19000980005 to R.B.).

**Acknowledgments:** The authors wish to thank Elena Bove for the graphic design of Figures 1 and 2 and for the creation of the graphic abstract.

**Conflicts of Interest:** The authors declare no conflict of interest.

**Footnote:** Figure 1 was modified by Holtan et al. [19] with kind permission by Publisher, License Number: 4911830648497.
