Neuropilin 2 has been identified as a novel regulator of distal colon smooth muscle motility

Neuropilin 2 has been identified as a novel regulator of distal colon smooth muscle motility

Intestinal motility disorders, particularly problems associated with constipation and diarrhea, are common in adults and children and significantly affect quality of life. A new study in the American Journal of Pathology published by Elsevier identifies neuropilin 2 (NRP2) as a novel regulator of distal colonic smooth muscle motility. Its ability to regulate cytoskeletal tone and curb abnormal smooth muscle contractions may provide future opportunities to inhibit or activate signaling and thereby regulate smooth muscle activity in patients suffering from colonic motility disorders.

“Normal visceral smooth muscle activity is central to the function of many body systems, including the gastrointestinal and urinary tracts, but is much less understood than vascular smooth muscle,” explained co-leader Maryrose P. Sullivan, PhD, Department of Surgery. Harvard Medical School; and Department of Urology, VA Boston Healthcare System, Boston, MA, USA. “Previous studies from our group showing strong expression of Nrp2 in colonic smooth muscle prompted us to understand its functional significance in contraction and colonic motility.”

The researchers found extensive NRP2 expression in the distal colon, which was particularly pronounced in circular and longitudinal smooth muscles in both human and mouse models. They used genetically engineered mice to determine the impact of Nrp2 deletion on colon contractility. After demonstrating extensive expression of Nrp2 in gastrointestinal smooth muscle, they determined the functional consequences of deleting the Nrp2 gene in vitro and analyzed motility in intact mice. Their results showed that colon tissue in mice with global or smooth muscle-specific deletion of Nrp2 had increased evoked contraction. Mice with inducible smooth muscle-specific Nrp2 deletion also showed an increase in colonic motility.

We were fascinated by the emergence of functional changes just one week after deletion of Nrp2. The relatively rapid detection of differences in the contractile behavior of the colon muscles argues against major structural changes in the tissue, but rather suggests changes in cellular signaling. Describing the signaling networks regulated by Nrp2 in smooth muscle is a key focus of our ongoing research.”

Rosalyn M. Adam, PhD, co-director, Urologic Diseases Research Center, Boston Children’s Hospital; and Department of Surgery, Harvard Medical School, Boston, MA, USA

Dr. Sullivan and Dr. Adam noted that their study represents an important contribution to understanding the mechanisms of visceral smooth muscle regulation and suggests that Nrp2 may be an actionable target in diseases characterized by abnormal smooth muscle contraction.

"Although studies in patients are still many years away, ongoing studies in our group are focused on developing small molecule inhibitors designed to inhibit Nrp2. These efforts may provide future opportunities to inhibit Nrp2 signaling and regulate smooth muscle activity in patients." is particularly relevant for diseases in which visceral smooth muscle is impaired, as no effective pharmacotherapy is currently available for these diseases,” they noted.

Changes in colonic motility can be due to a variety of conditions, including congenital anomalies such as Hirschsprung's disease, diabetes, inflammation, infection, intestinal dysbiosis, and nerve damage resulting from spinal injury. Furthermore, changes in the magnitude and/or coordination of contractile activity throughout the gastrointestinal tract can lead to impaired motility with resulting disruptions in intestinal flora, inflammation and nutrient absorption, often with serious health consequences.

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Reference:

Lambrinos, G., et al. (2022) Neuropilin 2 is a novel regulator of distal colon contractility. American Journal of Pathology. doi.org/10.1016/j.ajpath.2022.07.013.

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