PlGF Immunological Impact during Pregnancy

Abstract

During pregnancy, the mother's immune system has to tolerate the persistence of paternal alloantigens without affecting the anti-infectious immune response. Consequently, several mechanisms aimed at preventing allograft rejection, occur during a pregnancy. In fact, the early stages of pregnancy are characterized by the correct balance between inflammation and immune tolerance, in which proinflammatory cytokines contribute to both the remodeling of tissues and to neo-angiogenesis, thus, favoring the correct embryo implantation. In addition to the creation of a microenvironment able to support both immunological privilege and angiogenesis, the trophoblast invades normal tissues by sharing the same behavior of invasive tumors. Next, the activation of an immunosuppressive phase, characterized by an increase in the number of regulatory T (Treg) cells prevents excessive inflammation and avoids fetal immuno-mediated rejection. When these changes do not occur or occur incompletely, early pregnancy failure follows. All these events are characterized by an increase in different growth factors and cytokines, among which one of the most important is the angiogenic growth factor, namely placental growth factor (PlGF). PlGF is initially isolated from the human placenta. It is upregulated during both pregnancy and inflammation. In this review, we summarize current knowledge on the immunomodulatory effects of PlGF during pregnancy, warranting that both innate and adaptive immune cells properly support the early events of implantation and placental development. Furthermore, we highlight how an alteration of the immune response, associated with PlGF imbalance, can induce a hypertensive state and lead to the pre-eclampsia (PE).

Keywords: Flt-1/VEGFR1; PlGF; immune modulation; pregnancy.

Figure 1

Human placentation and malignancy share proliferative and invasive features to establish a nutrient supply and evade or modify the host’s immune response. (A) Human placenta development. In the early stage of implantation, the blastocyst displays an invasive phenotype that allows implanting inside the endometrial stroma. In this process cytokines, growth factors, hormones, extracellular matrix metalloproteinases (MMPs), and immune cells, all modulate cell invasion of maternal decidua and myometrium and their capacity to transform spiral arteries. Among growth factors, placental growth factor (PlGF) secreted by the decidua, trophoblast, and uterine natural killer (uNK) cells have a determinant role in regulating invasion, vascular development, and maternal immune tolerance mechanisms to semi-allogeneic fetus; (B) Tumor invasion and progression. Malignancy is able to create both a vascular network that warrants perfusion of tumor mass and an immunosuppressive microenvironment by recruiting specific immune cells. Molecules (cytokines, growth factors, extracellular MMPs), produced by tumor and inflammatory cells in the tumor microenvironment, recruit (tumor-associated) immune cells, thus, creating a tolerogenic milieu that inhibits the development of an efficient immune response against cancer cells that foster tumor growth and progression. PlGF blockade reduces both neoangiogenesis and lymphangiogenesis, inhibits the M2 macrophages polarization, hinders the recruitment of tumor-associated macrophages (TAM), and decreases the recruitment of myeloid suppressor cells [23]. (Illustration inspired by Holtan et al. [21] with kind permission of Elsevier, License Number: 4911830648497).

Figure 2

Reduced invasiveness and remodeling of maternal spiral arteries by trophoblastic cells is associated with a risk of pathological pregnancy.