Reduced Sympathetic Innervation in Endometriosis is Associated to Semaphorin 3C and 3F Expression

Abstract

Endometriosis is a chronic inflammatory disease and one of the most common causes of pelvic pain. The mechanisms underlying pain emergence or chronic inflammation during endometriosis remain unknown. Several chronic inflammatory diseases including endometriosis show reduced amounts of noradrenergic nerve fibers. The source of the affected innervation is still unclear. Semaphorins represent potential elicitors, due to their known role as axonal guidance cues, and are suggested as nerve repellent factors in different chronic inflammatory diseases. Therefore, semaphorins might influence the progress of neuroinflammatory mechanisms during endometriosis. Here, we analyzed the noradrenergic innervation and the expression of the specific semaphorins and receptors possibly involved in the neuroimmunomodulation in endometriosis. Our studies revealed an affected innervation and a significant increase of semaphorins and their receptors in peritoneal endometriotic tissue. Thereby, the expression of the receptors was identified on the membrane of noradrenergic nerve fibers and vessels. Macrophages 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, our data suggests that the chronic inflammatory condition in endometriosis might contribute to the increase of semaphorins, which could possibly affect the innervation in peritoneal endometriosis

Pathophysiology of endometriosis-associated pain: A review of pelvic and central nervous system mechanisms

“…Endometriosis patients with and without pain have been investigated, along with non-endometriosis controls, for nerve fibre density [34]. an increase in semaphorins and their receptors in peritoneal endometriotic tissue [35].…”

“…It has been suggested that semaphorins repel nerves in chronic inflammatory diseases, which could explain the reduced innervation by sympathetic nervous system [35].…”

Endometriosis - Pathogenesis and Sequelae

“…Elevated neuronal guidance molecules activities were observed in women with endometriosis. Women with endometriosis showed a significantly higher Semaphorin 3A in endometrium, Semaphorin 3C in the endometrium and peritoneal endometriotic lesions and Semaphorin 3F in peritoneal endometriotic lesions [147][148][149]. Shen et al, reported a higher expression of Slit and Robo1 proteins, as well as an increased microvascular density, in cases of endometrioma recurrence [150].…”

Villainous role of estrogen in macrophage-nerve interaction in endometriosis

“…Macrophages are reported to be one of the sources of semaphorin 3A [ 69 ]. Semaphorin 3F and 3C are also demonstrated to be released from macrophages in endometriosis [ 70 ]. Their receptors (NRP1 and NRP2) are positive in noradrenergic nerve fibers, which is associated with reduced sympathetic innervation [ 70 ].…”

“…Semaphorin 3F and 3C are also demonstrated to be released from macrophages in endometriosis [ 70 ]. Their receptors (NRP1 and NRP2) are positive in noradrenergic nerve fibers, which is associated with reduced sympathetic innervation [ 70 ]. As an estrogen-dependent disease, upregulation of estrogen is found to result in an increased expression of semaphorin 3F and lead to a sympathetic denervation in the rat uterus [ 71 ].…”