Abstract
The human endometrium undergoes inflammation and tissue repair during menstruation. We hypothesized that the local availability of bioactive glucocorticoids plays an important role in immune cell-vascular cell interactions in endometrium during tissue repair at menstruation, acting either directly or indirectly via tissue resident macrophages. We sought to determine whether endometrial macrophages are direct targets for glucocorticoids; whether cortisol-treated macrophages have a paracrine effect on angiogenic gene expression by endometrial endothelial cells; and whether endometrial macrophages express angiogenic factors. Human endometrium (n = 41) was collected with ethical approval and subject consent. Donor peripheral blood monocyte-derived macrophages were treated with estradiol, progesterone, or cortisol. The effect of peripheral blood monocyte-derived macrophage secretory products on the expression of angiogenic RNAs by endothelial cells was examined. Immunofluorescence was used to examine localization in macrophages and other endometrial cell types across the menstrual cycle. Endometrial macrophages express the glucocorticoid receptor. In vitro culture with supernatants from cortisol-treated peripheral blood monocyte-derived macrophages resulted in altered endometrial endothelial cell expression of the angiogenic genes, CXCL2, CXCL8, CTGF, and VEGFC These data highlight the importance of local cortisol in regulating paracrine actions of macrophages in the endometrium. CXCL2 and CXCL8 were detected in endometrial macrophages in situ. The expression of these factors was highest in the endometrium during the menstrual phase, consistent with these factors having a role in endometrial repair. Our data have indicated that activation of macrophages with glucocorticoids might have paracrine effects by increasing angiogenic factor expression by endometrial endothelial cells. This might reflect possible roles for macrophages in endometrial repair of the vascular bed after menstruation.
Highlights
The endometrium is a complex multicellular steroid-target tissue that is repaired each month after menses without residual scarring or loss of function
The expression of MRs was detected in some endometrial cell types and in the positive control tissue but was not colocalized with CD68 macrophages (Fig. 1E–H), suggesting that the local increase in cortisol observed at menstruation has the potential to affect macrophage function via activation of GRs but not MRs
We validated the expression of these 69 genes using individual gene specific assays and found that the concentrations of mRNAs encoded by VEGFC, CTGF, CXCL2, and CXCL8 were all significantly altered by media from cortisol-treated macrophages (Fig. 2A–D), with no evidence of estradiol or progesterone eliciting a similar response to that of cortisol
Summary
The endometrium is a complex multicellular steroid-target tissue that is repaired each month after menses without residual scarring or loss of function. It provides an accessible in vivo human model of inflammation and efficient tissue repair. Constituent cell types in the endometrium include stromal, epithelial, vascular, and immune cells. Dynamic cell-to-cell dialogue is essential to execute efficient endometrial shedding and subsequent re-epithelialization and stromal expansion, processes that are steroid regulated. The ovarian steroid hormones estradiol and progesterone are well established as regulators of human endometrial function. We recently reviewed the evidence that macrophages secrete factors that can influence endometrial repair [2].
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