Abstract
It is increasingly evident that cytokines and growth factors produced in the decidua play a pivotal role in the regulation of the local immune microenvironment and the establishment of pregnancy. One of the major growth factors produced in the decidua is vascular endothelial growth factor (VEGF), which acts not only on endothelial cells, but also on multiple other cell types, including macrophages. We sought to determine whether decidua-derived VEGF affects macrophage recruitment and polarization using human endometrial/decidual tissue samples, primary human endometrial stromal cells (ESCs), and the human monocyte cell line THP1. In situ hybridization was used for assessment of local VEGF expression and immunohistochemistry was used for identification and localization of CD68-positive endometrial macrophages. Macrophage migration in culture was assessed using a transwell migration assay, and the various M1/M2 phenotypic markers and VEGF expression were assessed using quantitative real-time PCR (qRT-PCR). We found dramatic increases in both VEGF levels and macrophage numbers in the decidua during early pregnancy compared to the secretory phase endometrium (non-pregnant), with a significant increase in M2 macrophage markers, suggesting that M2 is the predominant macrophage phenotype in the decidua. However, decidual samples from preeclamptic pregnancies showed a significant shift in macrophage phenotype markers, with upregulation of M1 and downregulation of M2 markers. In THP1 cultures, VEGF treatment significantly enhanced macrophage migration and induced M1 macrophages to shift to an M2 phenotype. Moreover, treatment with conditioned media from decidualized ESCs induced changes in macrophage migration and polarization similar to that of VEGF treatment. These effects were abrogated by the addition of a potent VEGF inhibitor. Together these results suggest that decidual VEGF plays a significant role in macrophage recruitment and M2 polarization, and that inhibition of VEGF signaling may contribute to the shift in macrophage polarity observed in different pregnancy disorders, including preeclampsia.
Highlights
During embryo implantation the uterine endometrium becomes decidualized, an inflammatory process that involves transformation of endometrial stromal cells into specialized secretory cells, and an influx of a multitude of immune cells [1]
Emerging evidence suggests that macrophage homing to the decidua and phenotype switching is of paramount importance in the establishment and maintenance of pregnancy [43,44,45]
We show that vascular endothelial growth factor (VEGF) levels and macrophage numbers positively correlate in the decidua in early pregnancy
Summary
During embryo implantation the uterine endometrium becomes decidualized, an inflammatory process that involves transformation of endometrial stromal cells into specialized secretory cells, and an influx of a multitude of immune cells [1] These immune cells are believed to play a central role in setting the balance between immune tolerance and proinflammatory responses, which is critical for proper implantation and establishment of a viable pregnancy [2]. M1 macrophages produce pro-inflammatory cytokines, present antigens, and produce nitric oxide and reactive oxygen species, whereas M2 macrophages are responsible for immune tolerance and tissue remodeling [9] Both M1 and M2 macrophages are present in the uterine decidua during pregnancy but their relative numbers vary; after an initial inflammatory phase, when M1 macrophages predominate, decidual macrophages have a predominantly M2 phenotype until the onset of parturition [10]. Little is known about the factors that regulate macrophage differentiation and polarization during pregnancy
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