Inhibition of receptor activity-modifying protein 1 suppresses the development of endometriosis and the formation of blood and lymphatic vessels.

Neuroimmune interactions are involved in the development of endometriosis. Here, we examined the role of a neuropeptide, calcitonin gene-related peptide (CGRP), and its receptor, receptor activity-modifying protein (RAMP) 1, in growth of endometrial tissues and the formation of blood and lymphatic vessels in a mouse ectopic endometrial transplantation model. Endometrial fragments from donor wild-type (WT) mice transplanted into the peritoneal wall of recipient WT mice grew with increased density of blood and lymphatic vessels. When tissues from RAMP1-deficient (RAMP1-/- ) mice were transplanted into RAMP1-/- mice, implant growth and angiogenesis/lymphangiogenesis were decreased. CGRP was up-regulated in dorsal root ganglia, and CGRP+ nerve fibres were distributed into the implants from the peritoneum. RAMP1 was co-expressed with CD11b (macrophages) and S100A4 (fibroblasts), but did not co-localize with blood vessel endothelial cell marker CD31 or lymphatic vessel endothelial hyaluronan receptor (LYVE)-1. Cultured with CGRP, macrophages up-regulated vascular endothelial growth factor (VEGF)-A, VEGF-C and VEGF-D, whereas fibroblasts up-regulated VEGF-C, but not VEGF-A or VEGF-D, in a RAMP1-dependent manner. CGRP receptor antagonist CGRP8-37 inhibited growth of and angiogenesis/lymphangiogenesis within endometrial tissue implants. These results suggest that RAMP1 signalling is crucial for growth and angiogenesis/lymphangiogenesis in endometrial tissue. Blockade of RAMP1 is a potential tool for the treatment of endometriosis.