Colonic motility disorders, particularly problems associated with constipation and diarrhea, are common in adults and children, greatly affecting 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 limit abnormal smooth muscle contraction may provide future opportunities to inhibit or activate signaling and thereby regulate smooth muscle activity in patients with disorders. colonic motility.
“Normal visceral smooth muscle activity is central to the function of many bodily systems, including the gastrointestinal and urinary tracts, but is much less studied than vascular smooth muscle,” explained the co-principal investigator. Maryrose P. Sullivan, PhD, Department of Surgery, Harvard Medical School; and Division of Urology, VA Boston Healthcare System, Boston, MA, USA. “Previous studies by our group that showed robust expression of Nrp2 in colonic smooth muscle prompted us to understand its functional importance in colonic contraction and motility.”
The researchers found extensive expression of NRP2 in the distal colon that was particularly prominent in circular and longitudinal smooth muscle in humans and mice. They used genetically modified mice to determine the impact of Nrp2 deletion on colonic contractility. After demonstrating extensive expression of Nrp2 in smooth muscle of the gastrointestinal tract, they determined the functional consequences of Nrp2 gene deletion in vitro and motility analysis in intact mice. Their results showed that colonic tissues displayed increased evoked contraction in mice with global or smooth muscle-specific deletion of Nrp2. Mice with an inducible smooth muscle-specific Nrp2 deletion also showed increased colonic motility.
We were intrigued by the emergence of functional changes as early as one week after Nrp2 deletion. The relatively rapid detection of differences in colonic muscle contractile behavior argues against major structural changes in the tissue, but instead suggests changes in cell signaling. Delineating Nrp2-regulated signaling networks in smooth muscle is a major focus of our ongoing research.”
Rosalyn M. Adam, PhD, Co-Principal Investigator, Center for Urological Disease Research, Children’s Hospital Boston; and Department of Surgery, Harvard Medical School, Boston, MA, USA
Dr. Sullivan and Dr. Adam observed that their study provides an important addition to the understanding of visceral smooth muscle regulatory mechanisms and suggests that Nrp2 may be an exploitable target in diseases characterized by abnormal smooth muscle contraction.
“Although studies in patients are still numerous, ongoing studies in our group are focused on the development of small molecule inhibitors designed to inhibit Nrp2. These efforts may provide opportunities in the future to inhibit signaling via Nrp2 and regulating smooth muscle activity in patients is particularly relevant for diseases in which visceral smooth muscle is impaired, as effective pharmacotherapy for these conditions is not currently available,” they noted.
Alterations in colonic motility can result from a variety of conditions, including birth defects such as Hirschsprung’s disease, diabetes, inflammation, infection, intestinal dysbiosis, and nerve damage secondary to spinal cord injury. Additionally, changes in the magnitude and/or coordination of contractile activity throughout the gastrointestinal tract can lead to dysfunctional motility leading to disturbances in gut flora, inflammation, and nutrient absorption. , often with serious health consequences.
Lambrinos, G. et al. (2022) Neuropilin 2 is a novel regulator of distal colonic contractility. American Journal of Pathology. doi.org/10.1016/j.ajpath.2022.07.013.
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