Specialized pro-resolving mediators: key regulators in placental function and pregnancy complications

Abstract

Specialized pro-resolving mediators (SPMs) are bioactive lipids derived from essential fatty acids that play a key role in resolving inflammation and modulating immune responses, thereby maintaining tissue homeostasis in various physiological contexts, including pregnancy. In healthy pregnancies, inflammation is a biological response necessary for vascular remodeling, embryo implantation as well as delivery and an increase in SPMs such as lipoxin A4 (LXA4) and resolvin D1 (RvD1) supports homeostasis and facilitates inflammation resolution. However, pregnancy complications such as spontaneous abortion, fetal growth restriction (FGR), and preeclampsia are often associated with disrupted SPM levels and receptor activity. In spontaneous abortion, altered SPM levels are linked to impaired endometrial receptivity, defective trophoblast invasion, poor epithelial-to-mesenchymal transition, and enhanced inflammation. Similarly, FGR is associated with reduced LXA4 levels, which contribute to placental vascular dysfunction and impaired trophoblast migration. Preeclampsia is characterized by dysregulated SPM levels and a pro-inflammatory environment, indicating insufficient resolutive activity. Therapeutic approaches to enhance SPM levels, such as aspirin-triggered lipoxins and omega-3 fatty acid supplementation, have demonstrated potential benefits. However, inconsistent clinical outcomes highlight the need for personalized treatment strategies. This review explores the role of SPMs in pregnancy, focusing on their molecular mechanisms and the development of targeted supplementation strategies to optimize their protective effects in managing high-risk pregnancies. KEY MESSAGES: Physiological pregnancies involve a gradual increase in SPM levels. LXA4 and RvD1 may have a context-dependent role in placentation by negatively regulating endometrial decidualization, trophoblast EMT and invasion, which contributes to spontaneous abortion, while positively regulating endothelial function, trophoblast survival and M2-macrophage polarization, which supports pregnancy. SPMs are essential to preserve endothelial integrity and support trophoblast proliferation, and appear downregulated in FGR. Preeclampsia is correlated with dysregulated SPM levels and a reduced LXA4/TNFα ratio, which suggests insufficient anti-inflammatory action. Therapeutic strategies that enhance SPMs production such as aspirin and DHA supplementation show considerable promise, particularly in preventing complications in high-risk pregnancies.

Keywords: Inflammation; Lipoxin A4 (LXA4); Pregnancy complications; Pregnancy supplementation; Specialized pro-resolving mediators (SPMs).

Fig. 1

Biosynthetic pathways of SPMs leading to the production of lipoxins, resolvins, protectins, and maresins. SPMs are produced from their precursors arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Key enzymes such as 5-LOX, 12-LOX and 15-LOX mediate the production of bioactive lipid mediators. Major known SPM receptors are shown on the right. Also depicted is the role of aspirin in inducing the specific aspirin-triggered lipoxin pathway via COX-2

Fig. 2

SPM levels during pregnancy and pathological conditions. A Physiological trend of LXA4 and RvD1 levels across the three pregnancy trimestres. Data points represent mean concentrations in nM for each study. Distinct trends are observed for both mediators. B Mean differences in LXA4 levels (nM) compared to controls in their respetive studies, for pregnancies complicated by preeclampsia (PE) and fetal growth restriction (FGR). C Mean differences in RvD1 levels (nM) compared to controls for PE and FGR. Positive and negative differences are highlighted in the green and red areas, respectively

Fig. 3

Specialized Pro-resolving Mediators (SPMs) in the implantation and placentation phases of pregnancy. In the implantation phase, SPMs downregulate stromal decidualization markers (IGFBP-1, PRL), migration and proliferation factors (MMP9, HCG, pPI3 K/pAKT), and epithelial-mesenchymal transition (EMT), while increasing markers such as E-cadherin, β-catenin, vimentin, fibronectin, and VEGF. During placentation, SPMs promote macrophage activation and recruitment, support the M2 phenotype by increasing IL-10 production, and inhibit the NF-κB pathway. Furthermore, SPMs enhance capillary formation and mitigate adverse processes such as caspase-1 activation, trophoblast apoptosis, lipid peroxidation, endothelial hyperpermeability, and endothelial-polymorphonuclear cell (PMN) adhesion. Red arrows indicate downregulation while green arrows indicate upregulation. The figure label represents the cell types involved, including endometrial stromal cells (ESCs), human umbilical vein endothelial cells (HUVECs), trophoblasts, macrophages, and PMNs