Sensory Denervation Can Slow Growth of Endometriosis Lesions, Mouse Study Says

Sensory Denervation Can Slow Growth of Endometriosis Lesions, Mouse Study Says

Sensory denervation — the loss of nerve cells responsible for detecting external cues and transporting that information to the brain — can slow the development of endometriosis lesions and tissue scarring, a study in mice shows.

According to researchers, this may be caused by a blockage of the sensory nerve-derived substance P (SP) and neurokinin receptor 1 (NK1R) signaling pathway, a chemical cascade involved in tissue inflammation and a possible new therapy target.

The findings of the study, “Sensory nerve-derived neuropeptides accelerate the development and fibrogenesis of endometriosis,” were published in Human Reproduction.

Endometriosis is a chronic debilitating inflammatory disease caused by the abnormal growth of womb cells outside the uterus. It is estimated to affect 6%–10% of all women of reproductive age.

Normally, lesions caused by endometriosis are highly innervated. Scientists believe the formation of nerves is triggered by the production and release of molecules called neutrophins by the lesions and possibly by platelets. These neutrophins seem to promote the formation of sensory nerves at the expense of sympathetic nerves (nerves that innervate involuntary smooth muscles, glands, and the heart).

“The striking histological relationship between nerves and the extent of lesional fibrosis … raises the possibility that nerves, especially sensory nerves, may facilitate the development and fibrogenesis (wound repair associated with inflammation) of endometriosis. We hypothesized that denervation, especially sensory denervation, may decelerate the development and fibrogenesis of endometriosis,” the investigators stated.

To test this, researchers from Fudan University in China carried out three experiments in animal models of disease.

There were 143 healthy (wild-type) female mice and 24 female immunodeficient mice used in all experiments.

Endometriosis was induced by injecting womb cells from female mice donors into the abdominal walls of other female mice, while sympathetic and sensory chemical denervation was attained by treating animals with 6-hydroxydopamine (6-OHDA) or resiniferatoxin (RTX), respectively.

All animals were sacrificed either two or four weeks after the induction of endometriosis, depending on the experimental protocol.

In the first experiment, 21 female mice were randomly divided into three groups: those that underwent sympathetic denervation; those that underwent sensory denervation; and those that did not undergo any procedure (controls). The weight of lesions caused by endometriosis decreased by 43.2% and 68.7% in animals who underwent sympathetic and sensory denervation, respectively, compared to controls. Besides reducing the weight of lesions, sensory denervation also improved hyperalgesia (high sensitivity to pain) symptoms.

In the second experiment, 24 immunodeficient female mice were randomly assigned to three groups: those that underwent surgical denervation three days before the induction of endometriosis; those that underwent surgery three days after the induction of endometriosis; and those that underwent a sham surgery (control) three days before the induction of endometriosis.

Results showed that the weight of endometriosis lesions, the extent of tissue scarring and hyperalgesia all improved in animals that underwent denervation surgery both before and after the induction of endometriosis.

In the third experiment, 32 female mice were randomly divided into four groups: those treated with a saline solution one day after the induction of endometriosis (control); those treated with SP (an activator of NK1R) one day after the induction of endometriosis; those treated with aprepitant (a strong antagonist of NK1R) one day after the induction of endometriosis; and those treated with aprepitant one day after the induction of endometriosis.

Findings showed that lesions from mice treated with SP rapidly progressed, leading to extensive tissue scarring and hyperalgesia. Conversely, treatment with aprepitant seemed to decelerate the development of lesions and ameliorated symptoms of hyperalgesia.

“In summary, we have shown in this study that sensory denervation decelerates the development and fibrogenesis of endometriosis, likely through the suppression of the SP/NK1R signaling pathway in endometriotic lesions,” the investigators said.

“Our study demonstrates that sensory nerves are likely an active accessory to endometriotic cells to accelerate lesional development in addition to their traditionally perceived roles as pain transducers. Sensory nerves are yet another unindicted culprit in the development of endometriosis, and, as such, NK1R may be an admissible drug target for treating endometriosis,” they added.

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
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Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
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