Human chorionic gonadotropin triggers angiogenesis via the modulation of endometrial cell receptivity to interleukin 1: a new mechanism underlying embryo-maternal crosstalk

Abstract

Embryo implantation is orchestrated by embryonic and maternal signals. Secretion of interleukin 1 (IL1) in response to the receptive endometrium induces molecular changes that are essential for embryonic implantation. Our objective was to investigate whether human chorionic gonadotropin (hCG), a major embryonic signal, modulates endometrial stromal cell receptivity to IL1 and assess the impact on tissue remodeling and angiogenesis. Cell treatment with hCG and/or IL1 and assessment of cell receptivity to IL1 and angiogenesis in vitro. Expression of IL1 receptors and angiogenic factors was analyzed by ELISA and qRT-PCR. Endothelial cell proliferation was evaluated using 3H-thimidine incorporation into DNA. For microarray analysis, RNA quality was assessed using Agilent Bioanalyzer. Reverse transcription to cDNA, fragmentation, labeling and hybridization with Human Gene 1.0 ST arrays were performed according to Affymetrix protocols. Functional grouping was carried out using the Ingenuity Pathway Analysis (IPA). Some of the most significantly (P<0.01) regulated genes (≥3-fold) were chosen for validation by qRT-PCR. hCG (100 ng/ml) significantly downregulated IL1R2 expression (P<0.01) in stromal cells; and effect which was maintained in cells subsequently exposed to IL1 (P<0.01) and accompanied by a significant increase in IL1R1 expression (P<0.001), MCP1 secretion (P<0.0001) and endothelial cell growth-promoting activity (P<0.01). Functional grouping (IPA) revealed significant changes in angiogenesis/tissue remodeling, immuno-inflammatory and cell signaling pathways and identified several genes that may play an important role in embryo-maternal signaling. hCG modulates endometrial cell receptivity to IL1, and act in synergy with IL1 to promote angiogenesis and tissue remodeling and modulate immune function at the embryo-maternal interface. This reveals a new mechanism by which hCG sustains human pregnancy and promotes embryonic growth.