Sensory nerve fibers release molecules, called neuropeptides, that promote progression and the buildup of scar tissue in deep endometriosis, a study suggests.
The study, “Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis,” was published in the journal Scientific Reports.
Endometriosis can be classified as peritoneal, ovarian, or deeply infiltrative, depending on the regions affected.
Deep endometriosis is characterized by endometrial tissue that infiltrates various regions, such as the pelvic area, bladder, and intestinal canal. It also can invade the uterine-rectal region, causing other problems, such as difficult defecation and intestinal irritability.
Deep endometriosis is characterized by a high degree of scar (fibrotic) tissue deposition and is frequently highly innervated, but the underlying mechanisms remain unknown.
A team of researchers in Shanghai hypothesized that small signaling molecules released by sensory nerves, called neuropeptides, could promote the development of scar tissue in deep endometriosis.
They studied the role of two neuropeptides, called substance P (SP) and calcitonin gene related peptide (CGRP).
Adding SP or CGRP for 72 hours to endometriotic epithelial cells led to changes in the cell shape and increased the cells’ proliferation and invasive properties when compared to control (untreated) cells in vitro. These changes were accompanied by a significant loss of a protein called E-cadherin that acts as a glue that keeps cells together.
Long-term (12 days) exposure of human endometriotic stromal cells to either SP or CGRP induced cells to transition into myofibroblasts — the cells responsible for the synthesis and buildup of scar tissue (fibrosis) as the cells became positive for alpha-SMA, a marker of myofibroblasts.
The dorsal root ganglion, located in the spinal cord, contains the cell bodies of sensory neurons. Researchers tested whether incubating the cells with the liquid released from the sensory cells produced the same changes as they saw with SP or CGRP.
They extracted the dorsal root ganglion neurons from a rat and incubated the cells in the lab, after which they collected the medium (supernatant) where the cells were and added it to human endometriotic stromal cells. Four days of incubation increased the levels of markers of myofibroblasts, such as alpha-SMA, desmin, and oxytocin receptor.
Researchers then blocked the action of SP and CGRP by adding potent inhibitors to the receptors to which each neuropeptide binds to exert its function, called NK1R and CGRP receptors, respectively.
The results showed that neutralizing the action of SP or CGRP abrogated the changes induced by the supernatant of dorsal root ganglion neurons, namely the increased levels of myofibroblast markers. Also, neutralizing either SP, CGRP or both abolished almost entirely endometriotic epithelial cells’ proliferation and invasiveness.
Finally, researchers confirmed that deep endometriosis human lesions had a significantly higher number of nerve fibers than ovarian endometriotic lesions, and that this correlated with the expression of neuropeptide receptors, fibrosis, and severity of pain in women with endometriosis.
Overall, the study suggests that “sensory nerves play an important role in promoting the development and fibrogenesis of endometriosis,” researchers said, and that blocking receptors of neuropeptides, namely NK1R, is a potential therapeutic strategy for endometriosis.