The potential role of the αVβ3 integrin receptor in placental biology and normal and complicated pregnancies.

Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a pregnancy-associated condition caused by human platelet antigen (HPA) incompatibility between a pregnant person and the fetus. Maternal exposure to an incompatible paternally-inherited HPA can elicit the production of anti-HPA alloantibodies that can enter the fetal circulation through active placental transport. Subsequently, these antibodies can lead to fetal thrombocytopenia and bleeding, including intracranial hemorrhage (ICH) [ 78 ]. Most cases of FNAIT are mediated by antibodies directed against the HPA-1a epitope, formed by a single amino acid change, L33P, in the Plexin-Semaphorin-Integrin (PSI) domain of β3 [ 79 ]. Anti-HPA-1a antibodies can react with both αIIbβ3 and αVβ3. αVβ3 is minimally expressed on platelets, whereas αIIbβ3 is highly expressed on platelets, but is not expressed on other cell types. It has been reported that anti-HPA-1a antibodies that preferentially bind αVβ3 compared to αIIbβ3, are more commonly associated with FNAIT cases with ICH [ 80 ]. Therefore, it has been hypothesized that the occurrence of ICH may be mediated by interfering with αVβ3-dependent ligand binding, and/or by disrupting the αVβ3-VEGFR2 interaction [ 81 ]. This subset of antibodies might, therefore impair angiogenesis and/or endothelial cell barrier function, contributing to the occurrence of ICH [ 82 ]. Several studies have also found an increased incidence of FGR in anti-HPA-1a-associated FNAIT [ 83 , 84 ], which may reflect the effects of anti-HPA-1a antibodies with placental trophoblast cells expressing αVβ3 [ 85 ].

This review highlights the important role of αVβ3 integrin receptor throughout normal gestation. In addition, dysregulated activity of the αVβ3 receptor participates in the pathophysiological mechanisms underlying different placenta-mediated complications. Thus, regulation of integrin expression, upstream and downstream signaling cascades, and the potential rescue of αVβ3 deficiency by other integrin receptors in pregnancy, are all important areas for future studies to improve maternal and perinatal outcomes.

The integrin family of cell receptors are type 1 transmembrane heterodimers assembled by a set of 18 α chains and 8 β chains, into 24 separate receptors [ 1 ]. The integrin receptors are characterized by undergoing an activation process leading to a high-affinity ligand binding state in response to internal signals (inside-out signaling), followed by binding of ligand(s) which, in turn, leads to transmission of additional signals back into the cell (outside-in signaling) [ 1 ]. Integrin receptors play critical roles in numerous physiologic and pathologic processes in mammals, including development, immunity, thrombosis and hemostasis, inflammation, angiogenesis, tumor growth, and metastasis [ 1 ]. The αVβ3 integrin receptor is a multifunctional protein expressed on the membranes of a variety of cell types, including endothelial cells, vascular smooth muscle cells, osteoclasts, and tumor cells [ 2 , 3 ]. It is involved in cell adhesion and migration, angiogenesis, immune cell regulation, bone resorption, renal podocyte function, and tumor progression [ 4 - 7 ]. αVβ3’s interactions with both the extracellular matrix (ECM) and the cytoskeleton are vital to many of its functions [ 8 ] ( Figure 1 ). In the ECM, αVβ3 recognizes the conserved tripeptide sequence Arg-Gly-Asp (RGD) found in many ECM proteins, including fibronectin and vitronectin [ 8 ]. A wide variety of mechanisms contribute to the normal development of the placenta and progression of pregnancy, including cell adhesion and migration, angiogenesis, and immune cell regulation, and thus, αVβ3 may participate in different stages of placental development and in its normal function. In this focused review, we summarize the literature on the potential roles of αVβ3 integrin receptor in normal pregnancies and in pregnancy-related pathological conditions based on a search of the literature in PubMed using the search terms “αVβ3 and pregnancy” and “αVβ3 and placenta”. The key roles of αVβ3 in normal and complicated pregnancies are summarized in Table 1 .