*5.2. Semaphorins and Neuromodulation*

The semaphorin family of proteins includes many secreted and membrane-associated proteins. There are approximately 20 distinct members in higher vertebrates, and all contain the family's signature semaphorin domain, a ~500 amino acid N-terminal that is the key extracellular signalling domain of these proteins. Semaphorins act as nerverepulsive factors that become extracellularly effective through a specific repulsive influence on either sympathetic or primary afferent sensitive fibres through various surface receptors, neuropilin-1 (Nrp1), and neuropilin-2 (Nrp2) [49,50].

In normal human endometrial tissue, the expression of many semaphorins is upregulated in the proliferative stage of the menstrual cycle, when estrogen is at its highest [39]. Estrogen has been found to induce the expression of semaphorins in uterine tissue [51]. Semaphorins 3C and 3F (Sema 3C and Sema 3F, respectively), in particular, are known as nerve repellent factors and are upregulated in EM-associated Mϕ in rat and mouse models [51,52]. In women with EM, studies revealed an affected innervation and a significant increase of Sema 3C and 3F and their receptors in peritoneal endometriotic tissue. Thereby, the expression of the receptors was identified on the membrane of noradrenergic nerve fibres and vessels. Mϕ and activated fibroblasts were found in higher density levels and additionally express semaphorins in peritoneal endometriotic tissue. Inflammation leads to an increased release of immune cells, which secrete a variety of inflammatory factors capable of affecting innervation. Therefore, these data suggest that the chronic inflammatory condition in EM might contribute to the increase of semaphorins, which could affect the innervation in peritoneal EM [53,54].
