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Netrin-1 is an extracellular guidance cue of neuronal navigation, mediated through interaction with its main receptors, and is known to be crucial in the development of multiple chronic inflammatory diseases. However, the expression pattern and mechanism of netrin-1 in endometriosis are currently undefined. Here we report that netrin-1 expression peaked in peritoneal macrophages found in endometriosis. Netrin-1 induced angiogenesis in ovarian endometriomas through interaction with CD146 in vascular endothelial cells. Through another receptor, neogenin, netrin-1 promoted neurite growth and sensitization in endometriosis through the up-regulation of MAP4, TAU, and CGRP. Targeted knockdown of neogenin in dorsal root ganglion (DRG) nerve cells compromised its response to netrin-1 through inhibiting phosphorylation of ERK1/2. The inhibition of netrin-1 using a neutralizing antibody reduced vascular and nerve infiltration in rat endometriotic lesions. In summary, our results suggest that netrin-1 is an important factor that promotes neuroangiogenesis in endometriosis. • Netrin-1 is overexpressed in macrophages found in endometriosis. • Netrin-1 promotes neuroangiogenesis, thereby fostering the pathogenesis and development of endometriosis. • Netrin-1 facilitates sensory nerve infiltration and sensitization via its receptor neogenin through the MAPK pathway. [ABSTRACT FROM AUTHOR]

This study demonstrates that the crosstalk between endometrial cells and mast cells promotes the migratory ability of endometrial epithelial and stromal cells and angiogenesis via CCL8/CCR1, thereby contributing to the development of endometriosis. • Endometrial cells promote the secretion of CCL8 from mast cells by their crosstalk. • CCL8 promotes the migratory ability of endometrial cells and novel angiogenesis. • CCL8 takes its effects via CCL8/CCR1. • CCR1 antagonist suppresses the development of endometriosis. The density and the activity of mast cells are associated with endometriosis. However, the role of mast cells on the pathogenesis of endometriosis remains unclear. Our study aims to investigate whether endometrial cells interact with mast cells and the involvement of their crosstalk in the development of endometriosis. The transwell assay was applied to investigate the effect of mast cells on the migratory ability of human primary endometrial cells. Mast cells were cocultured with endometrial epithelial and stromal cells respectively and total RNAs were isolated and subjected to mRNA sequencing. Next, the transwell assay, CCK-8, and tube formation were applied to study the role of CCL8 on the endometrial and endothelial cells in vitro. The mouse model was also established to confirm the role of CCL8 in the development and angiogenesis of endometriosis. CCL8 was up-regulated in mast cells when cocultured with endometrial cells. CCL8 was highly expressed in the ectopic endometrium and the serum of patients with endometriosis. CCL8 promoted the migratory ability of endometrial epithelial and stromal cells and increased the proliferation, migration, and tube formation of endothelial cells. CCR1, the receptor of CCL8, was over-expressed in the ectopic endometrium and colocalized with blood vessels in ovarian endometriomas. The inhibition of CCR1 suppressed the development and angiogenesis of endometriosis in vivo. The crosstalk between endometrial cells and mast cells in the development of endometriosis via CCL8/CCR1 was demonstrated, thereby providing a new treatment strategy for endometriosis. [ABSTRACT FROM AUTHOR]